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1.	Galka, Frank, et al. (författare) Proteomic characterization of the whole secretome of Legionella pneumophila and functional analysis of outer membrane vesicles. 2008 Ingår i: Infection and immunity. - 1098-5522. ; 76:5, s. 1825-36 Tidskriftsartikel (refereegranskat)abstract Secretion of effector molecules is one of the major mechanisms by which the intracellular human pathogen Legionella pneumophila interacts with host cells during infection. Specific secretion machineries which are responsible for the subfraction of secreted proteins (soluble supernatant proteins [SSPs]) and the production of bacterial outer membrane vesicles (OMVs) both contribute to the protein composition of the extracellular milieu of this lung pathogen. Here we present comprehensive proteome reference maps for both SSPs and OMVs. Protein identification and assignment analyses revealed a total of 181 supernatant proteins, 107 of which were specific to the SSP fraction and 33 of which were specific to OMVs. A functional classification showed that a large proportion of the identified OMV proteins are involved in the pathogenesis of Legionnaires' disease. Zymography and enzyme assays demonstrated that the SSP and OMV fractions possess proteolytic and lipolytic enzyme activities which may contribute to the destruction of the alveolar lining during infection. Furthermore, it was shown that OMVs do not kill host cells but specifically modulate their cytokine response. Binding of immunofluorescently stained OMVs to alveolar epithelial cells, as visualized by confocal laser scanning microscopy, suggested that there is delivery of a large and complex group of proteins and lipids in the infected tissue in association with OMVs. On the basis of these new findings, we discuss the relevance of protein sorting and compartmentalization of virulence factors, as well as environmental aspects of the vesicle-mediated secretion.
2.	Sekine, Takuya, et al. (författare) TOX is expressed by exhausted and polyfunctional human effector memory CD8(+) T cells 2020 Ingår i: Science immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 5:49 Tidskriftsartikel (refereegranskat)abstract CD8(+) T cell exhaustion is a hallmark of many cancers and chronic infections. In mice, T cell factor 1 (TCF-1) maintains exhausted CD8(+) T cell responses, whereas thymocyte selection-associated HMG box (TOX) is required for the epigenetic remodeling and survival of exhausted CD8(+) T cells. However, it has remained unclear to what extent these transcription factors play analogous roles in humans. In this study, we mapped the expression of TOX and TCF-1 as a function of differentiation and specificity in the human CD8(+) T cell landscape. Here, we demonstrate that circulating TOX+ CD8(+) T cells exist in most humans, but that TOX is not exclusively associated with exhaustion. Effector memory CD8(+) T cells generally expressed TOX, whereas naive and early-differentiated memory CD8(+) T cells generally expressed TCF-1. Cytolytic gene and protein expression signatures were also defined by the expression of TOX. In the context of a relentless immune challenge, exhausted HIV-specific CD8(+) T cells commonly expressed TOX, often in clusters with various activation markers and inhibitory receptors, and expressed less TCF-1. However, polyfunctional memory CD8(+) T cells specific for cytomegalovirus (CMV) or Epstein-Barr virus (EBV) also expressed TOX, either with or without TCF-1. A similar phenotype was observed among HIV-specific CD8(+) T cells from individuals who maintained exceptional immune control of viral replication. Collectively, these data demonstrate that TOX is expressed by most circulating effector memory CD8(+) T cell subsets and not exclusively linked to exhaustion.
3.	Afram, Gabriel, et al. (författare) Higher response rates in patients with severe chronic skin graft-versus-host disease treated with extracorporeal photopheresis 2019 Ingår i: Central European Journal of Immunology. - : TERMEDIA PUBLISHING HOUSE LTD. - 1426-3912 .- 1644-4124. ; 44:1, s. 84-91 Tidskriftsartikel (refereegranskat)abstract Introduction: Different forms of graft-versus-host disease (GVHD) remain a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The prognosis for steroid-refractory chronic GVHD (cGVHD) remains poor. Our aim was to evaluate extracorporeal photopheresis (ECP) treatment in cGVHD patients with different organ involvement to detect subgroups of patients with the best response.Material and methods: Thirty-four patients who underwent HSCT and developed moderate (n = 7) or severe (n = 27) steroid-refractory or steroid-dependent cGVHD treated with ECP were included in the analysis. A matched cGVHD control patient group untreated with ECP was collected for comparison.Results: Compared to the control group and the stable/progressive disease (SD/PD) patients, individuals with complete/partial remission have higher overall survival and lower transplant-related mortality. Furthermore, patients with complete and partial remission (CR/PR) had significantly higher levels of albumin and platelets after ECP treatment compared to patients with stable or progressive cGVHD (SD/PD). Corticosteroid treatment and other immunosuppressive agents could successfully be tapered in the CR/PR group compared to the SD/PD patients. In this study patients with skin cGVHD are those with the highest rate of CR/PR after ECP treatment.Conclusions: Our results suggest that ECP treatment is safe and effective for patients with predominantly skin, oral and liver cGVHD.
4.	Al Agrafi, Faisal, et al. (författare) Selective lysis of acute myeloid leukemia cells by CD34/CD3 bispecific antibody through the activation of γδ T-cells 2024 Ingår i: Oncoimmunology. - : Taylor and Francis Ltd.. - 2162-4011 .- 2162-402X. ; 13:1 Tidskriftsartikel (refereegranskat)abstract Despite the considerable progress in acute myeloid leukemia (AML) treatment, relapse after allogeneic hematopoietic stem cell transplantation (HSCT) is still frequent and associated with a poor prognosis. Relapse has been shown to be correlated with an incomplete eradication of CD34+ leukemic stem cells prior to HSCT. Previously, we have shown that a novel CD34-directed, bispecific T-cell engager (BTE) can efficiently redirect the T-cell effector function toward cancer cells, thus eliminating leukemic cells in vitro and in vivo. However, its impact on γδ T-cells is still unclear. In this study, we tested the efficacy of the CD34-specific BTE using in vitro expanded γδ T-cells as effectors. We showed that the BTEs bind to γδ T-cells and CD34+ leukemic cell lines and induce target cell killing in a dose-dependent manner. Additionally, γδ T-cell mediated killing was found to be superior to αβ T-cell mediated cytotoxicity. Furthermore, we observed that only in the presence of BTE the γδ T-cells induced primary AML blast killing in vitro. Importantly, our results show that γδ T-cells did not target the healthy CD34intermediate endothelial blood–brain barrier cell line (hCMEC/D3) nor lysed CD34+ HSCs from healthy bone marrow samples.
5.	Arruda, Lucas C. M., et al. (författare) A novel CD34-specific T-cell engager efficiently depletes acute myeloid leukemia and leukemic stem cells in vitro and in vivo 2022 Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 107:8, s. 1786-1795 Tidskriftsartikel (refereegranskat)abstract Less than a third of patients with acute myeloid leukemia (AML) are cured by chemotherapy and/or hematopoietic stem cell transplantation, highlighting the need to develop more efficient drugs. The low efficacy of standard treatments is associated with inadequate depletion of CD34(+) blasts and leukemic stem cells, the latter a drug-resistant subpopulation of leukemia cells characterized by the CD34(+)CD38(-) phenotype. To target these drug-resistant primitive leukemic cells better, we have designed a CD34/CD3 bi-specific T-cell engager (BTE) and characterized its anti-leukemia potential in vitro, ex vivo and in vivo. Our results show that this CD34-specific BTE induces CD34-dependent T-cell activation and subsequent leukemia cell killing in a dose-dependent manner, further corroborated by enhanced T-cell-mediated killing at the singlecell level. Additionally, the BTE triggered efficient T-cell-mediated depletion of CD34(+) hematopoietic stem cells from peripheral blood stem cell grafts and CD34(+) blasts from AML patients. Using a humanized AML xenograft model, we confirmed that the CD34-specific BTE had in vivo efficacy by depleting CD34(+) blasts and leukemic stem cells without side effects. Taken together, these data demonstrate that the CD34-specific BTE has robust antitumor effects, supporting development of a novel treatment modality with the aim of improving outcomes of patients with AML and myelodysplastic syndromes.
6.	Arruda, Lucas C. M., et al. (författare) Graft gamma delta T-cell receptor sequencing identifies public clonotypes associated to HSCT efficacy in AML patients and unravels CMV impact on repertoire distribution 2019 Ingår i: Bone Marrow Transplantation. - : NATURE PUBLISHING GROUP. - 0268-3369 .- 1476-5365. ; 54, s. 134-135 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
7.	Arruda, L. C. M., et al. (författare) Graft γδ TCR Sequencing Identifies Public Clonotypes Associated with Hematopoietic Stem Cell Transplantation Efficacy in Acute Myeloid Leukemia Patients and Unravels Cytomegalovirus Impact on Repertoire Distribution 2019 Ingår i: Journal of Immunology. - : NLM (Medline). - 0022-1767 .- 1550-6606. ; 202:6, s. 1859-1870 Tidskriftsartikel (refereegranskat)abstract Although the impact of donor graft composition on clinical outcomes after hematopoietic stem cell transplantation (HSCT) has been studied, little is known about the role of intragraft γδ TCR repertoire on clinical outcomes following HSCT. Using a high-throughput sequencing platform, we sought to analyze the TCR γ-chain (TRG) repertoire of γδ T cells within donor stem cell grafts and address its potential impact on clinical response in the corresponding patients. A total of 20 peripheral blood stem cell grafts were analyzed, and donors were classified as CMV+/- The respective acute myeloid leukemia recipients were followed for disease relapse and acute graft-versus-host disease (aGvHD) development post-HSCT. In all samples, TRG repertoire showed a reduced diversity and displayed overrepresented clones. This was more prominent in grafts from CMV+ donors, which presented a more private repertoire, lower diversity, skewed distribution, and reduced usage of the V9-JP pairing. Grafts given to nonrelapse patients presented a more public repertoire and increased presence of long sequence clonotypes. Variable-joining gene segment usage was not associated with aGvHD development, but a higher usage of V2-JP1 pairing and lower usage of V4-J2/V5-J2/V8-JP2 were observed in grafts given to nonrelapse patients. Our work identified five private overrepresented and one public CDR3 sequence (CATWDGPYYKKLF) associated with CMV infection, in addition to 12 highly frequent public sequences present exclusively in grafts given to nonrelapse patients. Our findings show that, despite CMV infection reshaping the TRG repertoire, TRG composition is not associated with aGvHD development, and several public sequences are associated with clinical remission.
8.	Arruda, Lucas C. M., et al. (författare) Impact of gamma delta T cells on clinical outcome of hematopoietic stem cell transplantation : systematic review and meta-analysis 2019 Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 3:21, s. 3436-3448 Forskningsöversikt (refereegranskat)abstract Allogeneic hematopoietic stem cell transplantation (HSCT) using alpha beta T-/B-cell-depleted grafts recently emerged as a transplant strategy and highlighted the potential role of gamma delta T cells on HSCT outcomes. Our aim was to scrutinize available evidence of gamma delta T-cell impact on relapse, infections, survival, and acute graft-versus-host disease (aGVHD). We performed a systematic review and meta-analysis of studies assessing gamma delta T cells in HSCT. We searched PubMed, Web of Science, Scopus, and conference abstracts from inception to March 2019 for relevant studies. We included all studies that assessed gamma delta T cells associated with HSCT. Data were extracted independently by 2 investigators based on strict selection criteria. A random-effects model was used to pool outcomes across studies. Primary outcome was disease relapse. We also assessed infections, survival, and aGVHD incidence. The review was registered with PROSPERO (CRD42019133344). Our search returned 2412 studies, of which 11 (919 patients) were eligible for meta-analysis. Median follow-up was 30 months (interquartile range, 22-32). High gamma delta T-cell values after HSCT were associated with less disease relapse (risk ratio [RR], 0.58; 95% confidence interval [95% CI], 0.40-0.84; P = .004; I-2 = 0%), fewer viral infections (RR, 0.59; 95% CI, 0.43-0.82; P < .002; I-2 = 0%) and higher overall (HR, 0.28; 95% CI, 0.18-0.44; P < .00001; I-2 = 0%) and disease-free survivals (HR 0.29; 95% CI, 0.18-0.48; P < .00001; I-2 = 0%). We found no association between high gd T-cell values and aGVHD incidence (RR, 0.72; 95% CI, 0.41-1.27; P = .26; I-2 = 0%). In conclusion, high gd T cells after HSCT is associated with a favorable clinical outcome but not with aGVHD development, suggesting that gd T cells have a significant effect on the success of HSCT. This study was registered with PROSPERO as #CRD42019133344.
9.	Arruda, L. C. M., et al. (författare) SARS-CoV-2 (COVID-19)-specific T cell and B cell responses in convalescent rheumatoid arthritis : Monozygotic twins pair case observation 2022 Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 95:5 Tidskriftsartikel (refereegranskat)abstract Rheumatoid arthritis (RA) patients present higher risk of SARS-CoV-2 infection (COVID-19), and proper management of the disease in this population requires a better understanding of how the immune system controls the virus. We analyzed the T cell and B cell phenotypes, and their repertoire in a pair of monozygotic twins with RA mismatched for COVID-19 infection. Twin- was not infected, while Twin+ was infected and effectively controlled the infection. We found no significant changes on the αβ T cell composition, while γδ T cells and B cells presented considerable expansion of memory population in Twin+ and robust T/B cell responses to several SARS-CoV-2 peptides. T cell receptor β/γ-chain and immunoglobulin heavy chain next-generation sequencing depicted a remarkable higher diversity in Twin+ compared with Twin-, despite no significant changes being found in variable/joining family usage. Repertoire overlap analyses showed that, although being identical twins, very few clones were shared between them, indicating that COVID-19 may lead to deep changes on the immune cell repertoire in RA patients. Altogether, our results indicate that RA patients may develop robust and persistent COVID-19-specific T/B cell responses; γδ T cells and B cells may play a key role in the management of COVID-19 in RA, and the infection may lead to a profound reshaping of immune cell receptor specificities.
10.	Berglund, S., et al. (författare) Advances in umbilical cord blood cell therapy : the present and the future 2017 Ingår i: Expert Opinion on Biological Therapy. - : Taylor & Francis. - 1471-2598 .- 1744-7682. ; 17:6, s. 691-699 Forskningsöversikt (refereegranskat)abstract Introduction: Umbilical cord blood (UCB), previously seen as medical waste, is increasingly recognized as a valuable source of cells for therapeutic use. The best-known application is in hematopoietic stem cell transplantation (HSCT), where UCB has become an increasingly important graft source in the 28 years since the first umbilical cord blood transplantation (UCBT) was performed. Recently, UCB has been increasingly investigated as a putative source for adoptive cell therapy. Areas covered: This review covers the advances in umbilical cord blood transplantation (UCBT) to overcome the limitation regarding cellular dose, immunological naivety and additional cell doses such as DLI. It also provides an overview regarding the progress in adoptive cellular therapy using UCB. Expert opinion: UCB has been established as an important source of stem cells for HSCT. Successful strategies to overcome the limitations of UCBT, such as the limited cell numbers and naivety of the cells, are being developed, including novel methods to perform in vitro expansion of progenitor cells, and to improve their homing to the bone marrow. Promising early clinical trials of adoptive therapies with UCB cells, including non-immunological cells, are currently performed for viral infections, malignant diseases and in regenerative medicine.
11.	Berglund, Sofia, et al. (författare) Expansion of Gammadelta T Cells from Cord Blood : A Therapeutical Possibility 2018 Ingår i: STEM CELLS INTERNATIONAL. - : HINDAWI LTD. - 1687-966X .- 1687-9678. Tidskriftsartikel (refereegranskat)abstract Gammadelta (gamma delta) T cells are found in both blood and tissues and have antiviral and antitumor properties. The frequency of gamma delta T cells in umbilical cord blood (UCB) is low, and the majority express delta 1, in contrast to blood, whereas the main subset is delta 2 gamma 9 T cells. UCB gamma delta T cells are functionally immature, which together with their scarcity complicates the development of UCB gamma delta T cell therapies. We aimed to develop an effective expansion protocol for UCB gamma delta T cells based on zoledronate and IL-2. We found that culture with 5 mu M zoledronate and 200 IU IL-2/ml medium for 14 days promoted extensive proliferation. The majority of the cultured cells were gamma 9 delta 2 T cells. The fold expansion of this, originally infrequent, subset was impressive (median and maximum fold change 253 and 1085, resp.). After culture, the cells had a polyclonal gamma delta T cell repertoire and the main memory subset was central memory (CD45RO(+) CD27(+)). The cells produced cytokines such as IL-1B, IL-2, and IL-8 and displayed significant tumor-killing capacity. These results show that development of in vitro expanded UCB gamma delta T cell therapies is feasible. It could prove a valuable treatment modality for patients after umbilical cord blood transplantation.
12.	Berglund, Sofia, et al. (författare) Granulocyte transfusions could benefit patients with severe oral mucositis after allogeneic hematopoietic stem cell transplantation 2019 Ingår i: Vox Sanguinis. - : Wiley-Blackwell. - 0042-9007 .- 1423-0410. ; 114:7, s. 769-777 Tidskriftsartikel (refereegranskat)abstract Background and objectives Mucositis is a common complication after allogeneic hematopoietic stem cell transplantation (HSCT), and is caused by a combination of conditioning-induced mucosal damage and severe neutropenia. The symptoms include oral and abdominal pain, inability to swallow food and fluids, and severe diarrhoea. Severe mucositis is associated with increased risk of Graft-versus-Host disease and infection. Granulocyte transfusions (GCX) could be a treatment option, and our objective was to study its feasibility and potential benefits. Material and methods This retrospective, single-centre study included 30 patients receiving GCX because of severe oral mucositis after HSCT during 2005-2017. Clinical outcome, response to GCX, change in opiate administration and adverse events were studied. Results Twenty-seven patients received GCX from donors pre-treated with steroids and G-CSF, and three from donors pre-treated with steroids only. Overall response was 83% (24/29 evaluable patients). Fifteen patients reached a complete response. In 14 of 24 responders, a reduction of the administration of opiate pain relief was seen. In eight patients this reduction was >= 50% of the dose. Adverse events (AEs) were reported in 14 cases, and were mild to moderate, and well manageable with symptomatic treatment. No life-threatening or fatal AEs were recorded. Conclusions These results indicate that GCX could be a safe and effective treatment for oral mucositis after HSCT with the potential to reduce the necessity of opiate analgesic treatment in this disorder. No severe AEs were seen in this study, but the risk for severe pulmonary AEs after GCX needs to be considered.
13.	Demuth, Andreas, et al. (författare) Pathogenomics: An updated European Research Agenda 2008 Ingår i: Infection, Genetics and Evolution. - : Elsevier BV. - 1567-7257 .- 1567-1348. ; 8:3, s. 386-393 Tidskriftsartikel (refereegranskat)abstract The emerging genomic technologies and bioinformatics provide novel opportunities for studying life-threatening human pathogens and to develop new applications for the improvement of human and animal health and the prevention, treatment, and diagnosis of infections. Based on the ecology and population biology of pathogens and related organisms and their connection to epidemiology, more accurate typing technologies and approaches will lead to better means of disease control. The analysis of the genome plasticity and gene pools of pathogenic bacteria including antigenic diversity and antigenic variation results in more effective vaccines and vaccine implementation programs. The study of newly identified and uncultivated microorganisms enables the identification of new threats. The scrutiny of the metabolism of the pathogen in the host allows the identification of new targets for anti-infectives and therapeutic approaches. The development of modulators of host responses and mediators of host damage will be facilitated by the research on interactions of microbes and hosts, including mechanisms of host damage, acute and chronic relationships as well as commensalisms. The study of multiple pathogenic and non-pathogenic microbes interacting in the host will improve the management of multiple infections and will allow probiotic and prebiotic interventions. Needless to iterate, the application of the results of improved prevention and treatment of infections into clinical tests will have a positive impact on the management of human and animal disease. The Pathogenomics Research Agenda draws on discussions with experts of the Network of Excellence "EuroPathoGenomics" at the management board meeting of the project held during 18-21 April 2007, in the Villa Vigoni, Menaggio, Italy. Based on a proposed European Research Agenda in the field of pathogenomics by the ERA-NET PathoGenoMics the meeting's participants updated the established list of topics as the research agenda for the future.
14.	Emelie, Radestad, et al. (författare) Individualization of hematopoietic stem cell transplantation using alpha/ beta depletion 2017 Ingår i: Scandinavian Journal of Immunology. - : WILEY. - 0300-9475 .- 1365-3083. ; 86:4, s. 338-338 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
15.	Foord, Emelie, et al. (författare) Characterization of ascites- and tumor-infiltrating gamma delta T cells reveals distinct repertoires and a beneficial role in ovarian cancer 2021 Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 13:577 Tidskriftsartikel (refereegranskat)abstract The role of gamma delta T cells in antitumor immunity has been under investigation for the past two decades, but little is known about their contribution to clinical outcomes in patients. Here, we set out to define the clonotypic, phenotypic, and functional features of gamma delta T cells in peripheral blood, ascites, and metastatic tumor tissue from patients with advanced epithelial ovarian cancer. T cell receptor (TCR) sequencing of the gamma chain revealed that tumor-infiltrating gamma delta T cells have a unique and skewed repertoire with high TCR diversity and low clonality. In contrast, ascites-derived gamma delta T cells presented a lower TCR diversity and higher clonality, suggesting a TCR-dependent clonal focusing at this site. Further investigation showed that tumor samples had abundant gamma delta T cells with a tissue-resident, activation-associated phenotype, less usage of V gamma 9 and an impaired response to adaptive-associated stimuli, implying an innate-like activation pathway, rather than an adaptive TCR-engaging pathway, at these tumor sites. Furthermore, high gamma delta T cell cytokine responsiveness upon stimulation was associated with a favorable outcome for patients in terms of both overall survival and reduced residual tumor burden after primary surgery. Last, the functionality of gamma delta T cells and patient survival were negatively affected by the proportions of CD39-expressing T cells, highlighting the potential of CD39 as a target to improve gamma delta T cell responses and unleash their antitumor capabilities.
16.	Foord, Emelie, et al. (författare) Profound Functional Suppression of Tumor-Infiltrating T-Cells in Ovarian Cancer Patients Can Be Reversed Using PD-1-Blocking Antibodies or DARPin (R) Proteins 2020 Ingår i: Journal of Immunology Research. - : Hindawi Limited. - 2314-8861 .- 2314-7156. ; 2020 Tidskriftsartikel (refereegranskat)abstract PD-1/PD-L1 blockade has revolutionized the field of immunooncology. Despite the relative success, the response rate to anti-PD-1 therapy requires further improvements. Our aim was to explore the enhancement of T-cell function by using novel PD-1-blocking proteins and compare with clinically approved monoclonal antibodies (mAbs). We isolated T-cells from the ascites and tumor of 17 patients with advanced epithelial ovarian cancer (EOC) and analyzed the effects using the mAbs nivolumab and pembrolizumab and two novel engineered ankyrin repeat proteins (DARPin (R) proteins). PD-1 blockade with either mAb or DARPin (R) molecule significantly increased the release of IFN-gamma, granzyme B, IL-2, and TNF-alpha, demonstrating successful reinvigoration. The monovalent DARPin (R) protein was less effective compared to its bivalent equivalent, demonstrating that bivalency brings an additional benefit to PD-1 blockade. Overall, we found a higher fold increase of lymphokine secretion in response to the PD-1 blockade by tumor-derived T-cells; however, the absolute amounts were significantly lower compared to the release from ascites-derived T-cells. Our results demonstrate that PD-1 blockade can only partially reinvigorate functionally suppressed T-cells from EOC patients. This warrants further investigation preferably in combination with other therapeutics. The study provides an early pilot proof-of-concept for the potential use of DARPin (R) proteins as eligible alternative scaffold proteins to block PD-1.
17.	Gaballa, Ahmed, et al. (författare) Assessment of TREC, KREC and telomere length in long term survivors after allogeneic HSCT : the role of GVHD and graft source and evidence for telomere homeostasis in young recipients 2017 Ingår i: Scandinavian Journal of Immunology. - : WILEY. - 0300-9475 .- 1365-3083. ; 86:4, s. 265-265 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
18.	Gaballa, A., et al. (författare) Assessment of TREC, KREC and telomere length in long-term survivors after allogeneic HSCT : the role of GvHD and graft source and evidence for telomere homeostasis in young recipients 2018 Ingår i: Bone Marrow Transplantation. - : Nature Publishing Group. - 0268-3369 .- 1476-5365. ; 53:1, s. 69-77 Tidskriftsartikel (refereegranskat)abstract Reconstitution of the adaptive immune system following allogeneic hematopoietic stem cell transplantation is crucial for beneficial outcome and is affected by several factors, such as GvHD and graft source. The impact of these factors on immune reconstitution has been thoroughly investigated during the early phase after transplantation. However, little is known about their long-term effect. Similarly, leukocyte telomere length (TL) shortening has been reported shortly after transplantation. Nevertheless, whether TL shortening continues in long-term aspect is still unsettled. Here, we assessed T-cell receptor excision circle (TREC), kappa deleting recombination excision circle (KREC) and leukocyte TL in recipients and donors several years post transplantation (median 17 years). Our analysis showed that, recipients who received bone marrow (BM) as the graft source have higher levels of both TREC and KREC. Also, chronic GvHD affected TREC levels and TL but not KREC levels. Finally, we show that recipient's TL was longer than respective donors in a group of young age recipients with high KREC levels. Our results suggest that BM can be beneficial for long-term adaptive immune recovery. We also present supporting evidence for recipient telomere homeostasis, especially in young age recipients, rather than telomere shortening.
19.	Gaballa, Ahmed, et al. (författare) CD8(+)gamma delta T Cells Are More Frequent in CMV Seropositive Bone Marrow Grafts and Display Phenotype of an Adaptive Immune Response 2019 Ingår i: STEM CELLS INTERNATIONAL. - : HINDAWI LTD. - 1687-966X .- 1687-9678. ; 2019 Tidskriftsartikel (refereegranskat)abstract The role of gamma delta (gamma delta) T cells in human cytomegalovirus (HCMV) immune surveillance has been the focus of research interest for years. Recent reports have shown a substantial clonal proliferation of gamma delta T cells in response to HCMV, shedding light on the adaptive immune response of gamma delta T cells. Nevertheless, most efforts have focused on V delta 2(neg)gamma delta T cell subset while less attention has been given to investigate other less common gamma delta T cell subsets. In this regard, a distinct subpopulation of gamma delta T cells that expresses the CD8 coreceptor (CD8(+)gamma delta T cells) has not been thoroughly explored. Whether it is implicated in HCMV response and its ability to generate adaptive response has not been thoroughly investigated. In this study, we combined flow cytometry and immune sequencing of the TCR gamma-chain (TRG) to analyze in-depth bone marrow (BM) graft gamma delta T cells from CMV seropositive (CMV+) and CMV seronegative (CMV-) donors. We showed that the frequency of CD8(+)gamma delta T cells was significantly higher in CMV+ grafts compared to CMV- grafts (P<0.001). Further characterization revealed that CD8(+)gamma delta T cells from CMV+ grafts express V gamma 9(-) and preferentially differentiated from a naive to terminal effector memory phenotype (CD27(low/-)CD45RO(-)). In line with these findings, TRG immune sequencing revealed clonal focusing and reduced usage of the V gamma 9/JP gene segment in a CMV+ graft. Furthermore, CD8(+)gamma delta T cells showed an enhanced response to TCR/CD3 and cytokine stimulation in contrast to CD8(-)gamma delta T cells. We conclude that gamma delta T cells in BM grafts are reshaped by donor CMV serostatus and highlight the potential adaptive role of CD8(+)gamma delta T cells in HCMV immune response.
20.	Gaballa, Ahmed, et al. (författare) Evaluating Thymic Function After Human Hematopoietic Stem Cell Transplantation in the Personalized Medicine Era 2020 Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11 Forskningsöversikt (refereegranskat)abstract Hematopoietic stem cell transplantation (HSCT) is an effective treatment option for several malignant and non-malignant hematological diseases. The clinical outcome of this procedure relies to a large extent on optimal recovery of adaptive immunity. In this regard, the thymus plays a central role as the primary site forde novogeneration of functional, diverse, and immunocompetent T-lymphocytes. The thymus is exquisitely sensitive to several insults during HSCT, including conditioning drugs, corticosteroids, infections, and graft-vs.-host disease. Impaired thymic recovery has been clearly associated with increased risk of opportunistic infections and poor clinical outcomes in HSCT recipients. Therefore, better understanding of thymic function can provide valuable information for improving HSCT outcomes. Recent data have shown that, besides gender and age, a specific single-nucleotide polymorphism affects thymopoiesis and may also influence thymic output post-HSCT, suggesting that the time of precision medicine of thymic function has arrived. Here, we review the current knowledge about thymic role in HSCT and the recent work of genetic control of human thymopoiesis. We also discuss different transplant-related factors that have been associated with impaired thymic recovery and the use of T-cell receptor excision circles (TREC) to assess thymic output, including its clinical significance. Finally, we present therapeutic strategies that could boost thymic recovery post-HSCT.
21.	Gaballa, Ahmed, et al. (författare) Revisiting the Role of gamma delta T Cells in Anti-CMV Immune Response after Transplantation 2021 Ingår i: Viruses. - : MDPI AG. - 1999-4915. ; 13:6, s. 1031- Forskningsöversikt (refereegranskat)abstract Gamma delta (gamma delta) T cells form an unconventional subset of T lymphocytes that express a T cell receptor (TCR) consisting of gamma and delta chains. Unlike conventional alpha beta T cells, gamma delta T cells share the immune signature of both the innate and the adaptive immunity. These features allow gamma delta T cells to act in front-line defense against infections and tumors, rendering them an attractive target for immunotherapy. The role of gamma delta T cells in the immune response to cytomegalovirus (CMV) has been the focus of intense research for several years, particularly in the context of transplantation, as CMV reactivation remains a major cause of transplant-related morbidity and mortality. Therefore, a better understanding of the mechanisms that underlie CMV immune responses could enable the design of novel gamma delta T cell-based therapeutic approaches. In this regard, the advent of next-generation sequencing (NGS) and single-cell TCR sequencing have allowed in-depth characterization of CMV-induced TCR repertoire changes. In this review, we try to shed light on recent findings addressing the adaptive role of gamma delta T cells in CMV immunosurveillance and revisit CMV-induced TCR reshaping in the era of NGS. Finally, we will demonstrate the favorable and unfavorable effects of CMV reactive gamma delta T cells post-transplantation.
22.	Gaballa, Ahmed, et al. (författare) T-cell frequencies of CD8(+) gamma delta and CD27(+) gamma delta cells in the stem cell graft predict the outcome after allogeneic hematopoietic cell transplantation 2019 Ingår i: Bone Marrow Transplantation. - : NATURE PUBLISHING GROUP. - 0268-3369 .- 1476-5365. ; 54:10, s. 1562-1574 Tidskriftsartikel (refereegranskat)abstract The impact of intra-graft T cells on the clinical outcome after allogeneic hematopoietic cell transplantation has been investigated. Most previous studies have focused on the role of alpha beta cells while gamma delta cells have received less attention. It has been an open question whether gamma delta cells are beneficial or not for patient outcome, especially with regards to graft versus host disease. In this study, graft composition of.d cell subsets was analyzed and correlated to clinical outcome in 105 recipients who underwent allogeneic hematopoietic cell transplantation between 2013 and 2016. We demonstrate for the first time that grafts containing higher T-cell proportions of CD8(+) gamma delta cells were associated with increased cumulative incidence of acute graft versus host disease grade II-III (50% vs 22.6%; P = 0.008). Additionally, graft T-cell frequency of CD27(+) gamma delta cells was inversely correlated with relapse (P = 0.006) and CMV reactivation (P = 0.05). We conclude that clinical outcome after allogeneic hematopoietic cell transplantation is influenced by the proportions of distinct gamma delta cell subsets in the stem cell graft. We also provide evidence that CD8(+) gamma delta cells are potentially alloreactive and may play a role in acute graft versus host disease. This study illustrates the importance of better understanding of the role of distinct subsets of.d cells in allogeneic hematopoietic cell transplantation.
23.	Guldevall, Karolin, 1981-, et al. (författare) Microchip screening platform for assessment of cytotoxic effector cells Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Here we report a screening platform for assessment of the cytotoxic potential of individual natural killer (NK) or T cells within larger populations. Human primary NK cells or human Epstein-Barr virus (EBV)- specific T cells were distributed across a silicon-glass microchip containing 32 400 individual microwells loaded with target cells. Through fluorescence screening and automated image analysis the numbers of effector and live or dead target cells in each well could be assessed at different time-points after initial mixing. Cytotoxicity was also studied by time-lapse live-cell imaging in microwells quantifying the killing potential of individual NK cells. Although most resting NK cells (≈75%) were non-cytotoxic to the leukemia cell line K562, some NK cells were able to kill several (≥3) target cells within the 12 hours long experiment. We demonstrate that this assay can be used to enumerate and characterize cytotoxic cells, something that could find clinical applications, e.g. in the selection of donors for stem cell transplantation or generation of highly specific and cytotoxic cells for adoptive immunotherapy.
24.	Guldevall, Karolin, et al. (författare) Microchip screening Platform for single cell assessment of NK cell cytotoxicity 2016 Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 7 Tidskriftsartikel (refereegranskat)abstract Here, we report a screening platform for assessment of the cytotoxic potential of individual natural killer (NK) cells within larger populations. Human primary NK cells were distributed across a silicon-glass microchip containing 32,400 individual microwells loaded with target cells. Through fluorescence screening and automated image analysis, the numbers of NK and live or dead target cells in each well could be assessed at different time points after initial mixing. Cytotoxicity was also studied by time-lapse live-cell imaging in microwells quantifying the killing potential of individual NK cells. Although most resting NK cells (approximate to 75%) were non-cytotoxic against the leukemia cell line K562, some NK cells were able to kill several (>= 3) target cells within the 12-h long experiment. In addition, the screening approach was adapted to increase the chance to find and evaluate serial killing NK cells. Even if the cytotoxic potential varied between donors, it was evident that a small fraction of highly cytotoxic NK cells were responsible for a substantial portion of the killing. We demonstrate multiple assays where our platform can be used to enumerate and characterize cytotoxic cells, such as NK or T cells. This approach could find use in clinical applications, e.g., in the selection of donors for stem cell transplantation or generation of highly specific and cytotoxic cells for adoptive immunotherapy.
25.	Herold, Nikolas, et al. (författare) Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies 2017 Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 23:2, s. 256-263 Tidskriftsartikel (refereegranskat)abstract The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults'. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP)(2-5), which causes DNA damage through perturbation of DNA synthesis(6). Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment(7-9). Here we demonstrate that the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM domain and HD domain 1 (SAMHD1) promotes the detoxification of intracellular ara-CTP pools. Recombinant SAMHD1 exhibited ara-CTPase activity in vitro, and cells in which SAMHD1 expression was transiently reduced by treatment with the simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive to ara-C-induced cytotoxicity. CRISPR-Cas9-mediated disruption of the gene encoding SAMHD1 sensitized cells to ara-C, and this sensitivity could be abrogated by ectopic expression of wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models of AML lacking SAMHD1 were hypersensitive to ara-C, and treatment ex vivo with Vpx sensitized primary patient derived AML blasts to ara-C. Finally, we identified SAMHD1 as a risk factor in cohorts of both pediatric and adult patients with de novo AML who received ara-C treatment. Thus, SAMHD1 expression levels dictate patient sensitivity to ara-C, providing proof-of-concept that the targeting of SAMHD1 by Vpx could be an attractive therapeutic strategy for potentiating ara-C efficacy in hematological malignancies.
26.	Larsson, Linda, et al. (författare) Pathogen reduced red blood cells as an alternative to irradiated and washed components with potential for up to 42 days storage 2024 Ingår i: Blood Transfusion. - : SIMTIPRO Srl. - 1723-2007. ; 22:2, s. 130-139 Tidskriftsartikel (refereegranskat)abstract Background - The urgency of maintaining a safe and adequate blood supply is increasing. One approach to ensure a sufficient supply is to limit the outdating frequency of blood components. Pathogen inactivation technology was developed primarily to increase safety by preventing transmission of infectious diseases. The Intercept Blood System for pathogen reduction of red blood cells (RBC) has additional benefits such as inactivation of leucocytes and removal of plasma and storage debris through centrifugation. Irradiation and automated washing are detrimental to the RBC membrane and often implicate shortened shelf-life. We aimed to assess whether pathogen inactivation can replace RBC irradiation and washing to avoid shelf-life reduction. Materials and methods - RBC concentrates (No.=48) were pooled-and-split into four study arms, which underwent pathogen inactivation treatment, irradiation, automated washing or no treatment (reference). RBC quality was evaluated during 42 days by assessment of storage lesion. Washing efficacy was defined by IgA and albumin reduction. Results - Pathogen reduced RBCs had similar membrane preservation to reference RBCs (hemolysis, microvesicles and extracellular potassium ions), whereas the RBCs were negatively impacted by irradiation or automated washing. ATP increased substantially post-pathogen inactivation, while 2,3-DPG decreased. Pathogen inactivation considerably reduced albumin and IgA, though slightly less efficiently than automated washing. Discussion - RBCs exhibit superior membrane preservation after pathogen inactivation treatment, compared to both irradiation and automated washing. This suggests that replacement is possible, even though the plasma reduction protocol could be further optimised. Replacement of irradiated and washed RBC concentrates with pathogen reduced RBC concentrates storable up to 42 days would be advantageous for both the blood supply and patient safety.
27.	Leijonhufvud, Caroline, et al. (författare) Comprehensive Exploration of NK Cell Education in ADCC Triggered By a Monoclonal Antibody or a Bispecific Killer Engager Molecule (BiKE) 2022 Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 140, s. 8350-8350 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
28.	Matar, Amal, et al. (författare) A proposal for an international Code of Conduct for data sharing in genomics 2022 Ingår i: Developing World Bioethics. - : John Wiley & Sons. - 1471-8731 .- 1471-8847. ; 23:4, s. 344-357 Tidskriftsartikel (refereegranskat)abstract As genomic research becomes commonplace across the world, there is an increased need to coordinate practices among researchers, especially with regard to data sharing. One such way is an international code of conduct. In September 2020, an expert panel consisting of representatives from various fields convened to discuss a draft proposal formed via a synthesis of existing professional codes and other recommendations. This article presents an overview and analysis of the main issues related to international genomic research that were discussed by the expert panel, and the results of the discussion and follow up responses by the experts. As a result, the article presents as an annex a proposal for an international code of conduct for data sharing in genomics that is meant to establish best practices.
29.	Nair, Deepika, et al. (författare) Methylseleninic Acid Sensitizes Ovarian Cancer Cells to T-Cell Mediated Killing by Decreasing PDL1 and VEGF Levels 2018 Ingår i: Frontiers in Oncology. - : Frontiers Media S.A.. - 2234-943X. ; 8 Tidskriftsartikel (refereegranskat)abstract Redox active selenium (Se) compounds at sub toxic doses act as pro-oxidants with cytotoxic effects on tumor cells and are promising future chemotherapeutic agents. However, little is known about how Se compounds affect immune cells in the tumor microenvironment. We demonstrate that the inorganic Se compound selenite and the organic methylseleninic acid (MSA) do not, despite their pro-oxidant function, influence the viability of immune cells, at doses that gives cytotoxic effects in ovarian cancer cell lines. Treatment of the ovarian cancer cell line A2780 with selenite and MSA increases NK cell mediated lysis, and enhances the cytolytic activity of T cells. Increased T cell function was observed after incubation of T cells in preconditioned media from tumor cells treated with MSA, an effect that was coupled to decreased levels of PDL1, HIF-1 alpha, and VEGF. In conclusion, redox active selenium compounds do not kill or inactivate immune cells at doses required for anti-cancer treatment, and we demonstrate that MSA enhances T cell-mediated tumor cell killing via PDL1 and VEGF inhibition.
30.	Nilsson, J., et al. (författare) Functionality testing of stem cell grafts to predict infectious complications after allogeneic hematopoietic stem cell transplantation 2017 Ingår i: Vox Sanguinis. - : John Wiley & Sons. - 0042-9007 .- 1423-0410. ; 112:5, s. 459-468 Tidskriftsartikel (refereegranskat)abstract Background and Objectives Allogeneic hematopoietic stem cell transplantation (HSCT) is a routine clinical procedure performed to treat patients with haematological malignancies, primary immune deficiencies or metabolic disorders. Infections during lymphopenia after allogeneic HSCT are associated with high mortality and morbidity. Typical infectious agents are Epstein-Barr virus, cytomegalovirus, herpes simplex virus, varicella-zoster virus and fungi. The study aim was to evaluate whether measurement of the responses of antigen-specific T-cells, recognizing infectious pathogens would correlate to protective functions in the stem cell recipient post-transplant. Materials and MethodsTwenty-one grafts were analysed by flow cytometry and cells were stimulated in vitro with relevant infectious antigens, followed by evaluation of T-cell proliferation and cytokine production. Results were compared to the recipients' clinical records 1-year post-transplantation. ResultsWe show that an extensive repertoire of transferred antigen-specific T-cells from allogeneic donor grafts against infectious agents, involved in post-transplant infections, are linked to an absence of infectious complications for the recipient up-to 1-year post-transplant. The protective effect was associated with antigen-specific T-cell proliferation and IL-1 secretion. Conclusion Our results suggest that assaying T-cell function before HSCT could determine individual risks for infectious complications and thus aid in clinical decision-making regarding prophylactic and pre-emptive anti-infective therapy.
31.	Norström, Melissa M., et al. (författare) Progression of benign prostatic hyperplasia is associated with pro-inflammatory mediators and chronic activation of prostate-infiltrating lymphocytes 2016 Ingår i: Oncotarget. - : Impact Journals LLC. - 1949-2553. ; 7:17, s. 23581-23593 Tidskriftsartikel (refereegranskat)abstract Benign prostatic hyperplasia (BPH) is a common chronic non-malignant condition whose prevalence substantially increases with age. Immune cell infiltration and pro-inflammatory mediators have been implicated in the pathogenesis. Here, we characterized 21 extracellular markers on prostate-infiltrating lymphocytes (PILs) and analyzed expression of 26 soluble proteins in prostate tissue obtained from BPH patients (n = 31). These data were correlated with clinical parameters and compared with peripheral blood mononuclear cells (PBMCs) (n = 10). Increased frequencies of T cells expressing co-inhibitory receptors LAG-3, PD-1, TIM-3 or CTLA-4, and co-stimulatory receptors CD28, OX40 or 4-1BB were observed in BPH tissue compared to PBMCs. These findings are consistent with chronic activation and possible functional exhaustion of PILs that may be further augmented by several identified pro-inflammatory factors, such as IL-8 and MCP-1, promoting inflammation and chemotaxis of immune cells to the prostate. Prostate size and plasma prostate-specific antigen levels positively correlated with IL-8 and MCP-1 concentrations, and frequencies of T cells expressing CTLA-4 and TIM-3. It remains to be established whether the link between inflammation and BPH progression supported by our findings reflects a progressive failure of the immune system leading to decreased immune surveillance and development of prostate cancer.
32.	Radestad, Emelie, et al. (författare) Immune profiling and identification of prognostic immune-related risk factors in human ovarian cancer 2019 Ingår i: Oncoimmunology. - : TAYLOR & FRANCIS INC. - 2162-4011 .- 2162-402X. ; 8:2 Tidskriftsartikel (refereegranskat)abstract Suppression of immune reactivity by increased expression of co-inhibitory receptors has been discussed as a major reason as to why the immune system fails to control tumor development. Elucidating the co-inhibitory expression pattern of tumor-infiltrating lymphocytes in different cancer types will help to develop future treatment strategies. We characterized markers reflecting and affecting T-cell functionality by flow cytometry on lymphocytes isolated from blood, ascites and tumor from advanced ovarian cancer patients (n = 35). Significantly higher proportions of CD4+ and CD8+ T-cells expressed coinhibitory receptors LAG-3, PD-1 and TIM-3 in tumor and ascites compared to blood. Co-expression was predominantly observed among intratumoral CD8+ T-cells and the most common combination was PD-1 and TIM-3. Analysis of 26 soluble factors revealed highest concentrations of IP-10 and MCP-1 in both ascites and tumor. Correlating these results with clinical outcome revealed the proportion of CD8+ T-cells without expression of LAG-3, PD-1 and TIM-3 to be beneficial for overall survival. In total we identified eight immune-related risk factors associated with reduced survival. Ex vivo activation showed tumor-derived CD4+ and CD8+ T-cells to be functionally active, assessed by the production of IFN-gamma, IL-2, TNF-alpha, IL-17 and CD107a. Blocking the PD-1 receptor resulted in significantly increased release of IFN-. suggesting potential reinvigoration. The ovarian tumor environment exhibits an inflammatory milieu with abundant presence of infiltrating immune cells expressing inhibitory checkpoints. Importantly, we found subsets of CD8+ T-cells with double and triple expression of co-inhibitory receptors, supporting the need for multiple checkpoint-targeting agents to overcome T-cell dysfunction in ovarian cancer.
33.	Radestad, Emelie, et al. (författare) Individualization of Hematopoietic Stem Cell Transplantation Using Alpha/Beta T-Cell Depletion 2019 Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 10 Tidskriftsartikel (refereegranskat)abstract Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with several potentially lethal complications. Higher levels of CD3+ T-cells in the graft have been associated with increased risk of graft-versus-host disease (GVHD), but also beneficial graft-versus-leukemia effect and reduced infections. To tackle post-transplant complications, donor lymphocyte infusions have been used but with an increased risk of GVHD. To reduce this risk, we performed depletion of alpha beta T-cells and treated 12 patients post-HSCT suffering from infections and/or poor immune reconstitution. The alpha beta T-cell depleted cell products were characterized by flow cytometry. The median log depletion of alpha beta T-cells was -4.3 and the median yield of gamma delta T-cells was 73.5%. The median CD34+ cell dose was 4.4 x 10(6)/kg. All 12 patients were alive 3 months after infusion and after 1 year, two patients had died. No infusion-related side effects were reported and no severe acute GVHD (grade III-IV) developed in any patient post-infusion. Overall, 3 months after infusion 11 out of 12 patients had increased levels of platelets and/or granulocytes. In conclusion, we describe the use of alpha beta T-cell depleted products as stem cell boosters with encouraging results.
34.	Radestad, E., et al. (författare) Tumor-infiltrating T-cells of ovarian cancer express markers associated with functional impairment 2016 Ingår i: European Journal of Immunology. - : Wiley-Blackwell. - 0014-2980 .- 1521-4141. ; 46, s. 196-196 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
35.	Rasmusson, Ida, et al. (författare) Mesenchymal stem cells fail to trigger effector functions of cytotoxic T lymphocytes 2007 Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 0741-5400 .- 1938-3673. ; 82:4, s. 887-893 Tidskriftsartikel (refereegranskat)abstract Mesenchymal stem cells (MSCs), isolated from adult human bone marrow, have immunomodulatory properties. The functional outcomes of MSCs-CTL interactions remain poorly characterized. In this study, we demonstrate that MSCs remain resistant to CTL lysis, even after pulsing with the specific synthetic peptide at high concentrations, in spite of surface expression of the relevant MHC class I allele. MSCs were also much less sensitive to lysis by an allo-specific CTL clone as compared with HLA-matched lymphoblastoid cell lines. MSCs induced CD25 up-regulation, albeit at relatively low levels, and were unable to induce CD3 or CD8 down-regulation at the surface of CTLs. MSCs also failed to induce IFN-γ and TNF-α production by the CTLs. Furthermore, peptide-pulsed MSCs were inefficient in stimulating tyrosine phosphorylation in specific CTLs. Our results demonstrate that MSCs induce only an abortive activation program in fully differentiated, effector CTLs, which does not involve activation of major CTL effector functions. These data may have important implications for the development of therapeutic strategies based on administration of in vitro-expanded MSCs.
36.	Remberger, Mats, et al. (författare) Improved survival after allogeneic hematopoietic stem cell transplantation in recent years : A single-center study 2011 Ingår i: Biology of blood and marrow transplantation. - : Elsevier BV. - 1083-8791 .- 1523-6536. ; 17:11, s. 1688-1697 Tidskriftsartikel (refereegranskat)abstract We analyzed the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) over the past 2 decades. Between 1992 and 2009, 953 patients were treated with HSCT, mainly for a hematologic malignancy. They were divided according to 4 different time periods of treatment: 1992 to 1995, 1996 to 2000, 2001 to 2005, and 2006 to 2009. Over the years, many factors have changed considerably regarding patient age, diagnosis, disease stage, type of donor, stem cell source, genomic HLA typing, cell dose, type of conditioning, treatment of infections, use of granulocyte-colony stimulating factor (G-CSF), use of mesenchymal stem cells, use of cytotoxic T cells, and home care. When we compared the last period (2006-2009) with earlier periods, we found slower neutrophil engraftment, a higher incidence of acute graft-versus-host disease (aGVHD) of grades II-IV, and less chronic GVHD (cGHVD). The incidence of relapse was unchanged over the 4 periods (22%-25%). Overall survival (OS) and transplant-related mortality (TRM) improved significantly in the more recent periods, with the best results during the last period (2006-2009) and a 100-day TRM of 5.5%. This improvement was also apparent in a multivariate analysis. When correcting for differences between the 4 groups, the hazard ratio for mortality in the last period was 0.59 (95% confidence interval [CI]: 0.44-0.79; P < .001) and for TRM it was 0.63 (CI: 0.43-0.92; P = .02). This study shows that the combined efforts to improve outcome after HSCT have been very effective. Even though we now treat older patients with more advanced disease and use more alternative HLA nonidentical donors, OS and TRM have improved. The problem of relapse still has to be remedied. Thus, several different developments together have resulted in significantly lower TRM and improved survival after HSCT over the last few years.
37.	Rådestad, E., et al. (författare) Characterization of infiltrating lymphocytes in human benign and malignant prostate tissue 2017 Ingår i: Oncotarget. - : Impact Journals LLC. - 1949-2553. ; 8:36, s. 60257-60269 Tidskriftsartikel (refereegranskat)abstract Immune checkpoint blockade has shown promising results in numerous cancer types. However, in prostate cancer (PC), absent or limited responses have been reported. To investigate further, we compared the phenotype of infiltrating T-cells isolated from prostate tissue from patients with PC (n = 5), benign prostatic hyperplasia (BPH) (n = 27), BPH with concurrent PC (n = 4) and controls (n = 7). The majority of T-cells were CD8+ and had a CCR7-CD45RO+ effector memory phenotype. However, the yield of T-cells isolated from PC lesions was on average 20-fold higher than that obtained from control prostates. Furthermore, there were differences between the prostate conditions regarding the percentage of T-cells expressing several activation markers and co-inhibitory receptors. In conclusion, many prostateinfiltrating T-cells express co-inhibitory receptors PD-1 and LAG-3, regardless of prostate condition. Despite the observed increase in counts and percentages of PD- 1+ T-cells in PC, the concomitant demonstration of high percentage of PD-1+ T-cells in control prostates suggests that PD-1 may play a role in controlling the homeostasis of the prostate rather than in contributing to PC-associated immune-suppression. Thus, PD-1 may not be a good candidate for checkpoint blockade in PC and these data are relevant for evaluation of clinical trials and in designing future immunotherapeutic approaches of PC.
38.	Sandoz, Patrick, et al. (författare) Modulation of lytic molecules restrain serial killing in γδ T lymphocytes 2023 Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1 Tidskriftsartikel (refereegranskat)abstract γδ T cells play a pivotal role in protection against various types of infections and tumours, from early childhood on and throughout life. They consist of several subsets characterised by adaptive and innate-like functions, with Vγ9Vδ2 being the largest subset in human peripheral blood. Although these cells show signs of cytotoxicity, their modus operandi remains poorly understood. Here we explore, using live single-cell imaging, the cytotoxic functions of γδ T cells upon interactions with tumour target cells with high temporal and spatial resolution. While γδ T cell killing is dominated by degranulation, the availability of lytic molecules appears tightly regulated in time and space. In particular, the limited co-occurrence of granzyme B and perforin restrains serial killing of tumour cells by γδ T cells. Thus, our data provide new insights into the cytotoxic arsenal and functions of γδ T cells, which may guide the development of more efficient γδ T cell based adoptive immunotherapies.
39.	Sawaisorn, Piamsiri, et al. (författare) Human Vγ9Vδ2 T cell expansion and their cytotoxic responses against cholangiocarcinoma 2024 Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 14:1 Tidskriftsartikel (refereegranskat)abstract Human Vγ9Vδ2 T lymphocytes are regarded as promising effector cells for cancer immunotherapy since they have the ability to eliminate several tumor cells through non-peptide antigen recognition. However, the cytotoxic function and the mechanism of Vγ9Vδ2 T cells leading to specific killing of cholangiocarcinoma cells are yet to be confirmed. In this study, we established a protocol for ex vivo expansion of Vγ9Vδ2 T cells from healthy donors’ peripheral blood mononuclear cells by culture with zoledronate and addition of IL-2, and IL-15 or IL-18 or neither. Testing the cytotoxic capacity of cultured Vγ9Vδ2 T cells against cholangiocarcinoma cell lines showed higher reactivity than against control cells. Surface expression of CD107 was detected on the Vγ9Vδ2 T cells, suggesting that these cells limit in vitro growth of cholangiocarcinoma cells via degranulation of the perforin and granzyme pathway. Analysis of molecular signaling was used to demonstrate expression of pro- and anti-survival genes and a panel of cytokine genes in Vγ9Vδ2 T cells. We found that in the presence of either IL-15 or IL-18, levels of caspase 3 were significantly reduced. Also, IL-15 and IL-18 stimulated cells contained cytotoxicity against cholangiocarcinoma cells, suggesting that stimulated Vγ9Vδ2 T cells may provide a feasible therapy for cholangiocarcinoma.
40.	Stikvoort, Arwen, et al. (författare) Combining Flow and Mass Cytometry in the Search for Biomarkers in Chronic Graft-versus-Host Disease 2017 Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 8 Tidskriftsartikel (refereegranskat)abstract Chronic graft-versus-host disease (cGVHD) is a debilitating complication arising in around half of all patients treated with an allogeneic hematopoietic stem cell transplantation. Even though treatment of severe cGVHD has improved during recent years, it remains one of the main causes of morbidity and mortality in affected patients. Biomarkers in blood that could aid in the diagnosis and classification of cGVHD severity are needed for the development of novel treatment strategies that can alleviate symptoms and reduce the need for painful and sometimes complicated tissue biopsies. Methods that comprehensively profile complex biological systems such as the immune system can reveal unanticipated markers when used with the appropriate methods of data analysis. Here, we used mass cytometry, flow cytometry, enzyme-linked immunosorbent assay, and multiplex assays to systematically profile immune cell populations in 68 patients with varying grades of cGVHD. We identified multiple subpopulations across T, B, and NK-cell lineages that distinguished patients with cGVHD from those without cGVHD and which were associated in varying ways with severity of cGVHD. Specifically, initial flow cytometry demonstrated that patients with more severe cGVHD had lower mucosal-associated T cell frequencies, with a concomitant higher level of CD38 expression on T cells. Mass cytometry could identify unique subpopulations specific for cGVHD severity albeit with some seemingly conflicting results. For instance, patients with severe cGVHD had an increased frequency of activated B cells compared to patients with moderate cGVHD while activated B cells were found at a reduced frequency in patients with mild cGVHD compared to patients without cGVHD. Moreover, results indicate it may be possible to validate mass cytometry results with clinically viable, smaller flow cytometry panels. Finally, no differences in levels of blood soluble markers could be identified, with the exception for the semi-soluble combined marker B-cell activating factor/B cell ratio, which was increased in patients with mild cGVHD compared to patients without cGVHD. These findings suggest that interdependencies between such perturbed subpopulations of cells play a role in cGVHD pathogenesis and can serve as future diagnostic and therapeutic targets.
41.	Stikvoort, Arwen, et al. (författare) Identifying cellular subsets diagnostic for severity chronic GVHD 2017 Ingår i: Scandinavian Journal of Immunology. - : WILEY. - 0300-9475 .- 1365-3083. ; 86:4, s. 264-264 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
42.	Stikvoort, Arwen, et al. (författare) Risk Factors for Severe Acute Graft-versus-Host Disease in Donor Graft Composition 2018 Ingår i: Biology of blood and marrow transplantation. - : ELSEVIER SCIENCE INC. - 1083-8791 .- 1523-6536. ; 24:3, s. 467-477 Tidskriftsartikel (refereegranskat)abstract Acute graft-versus-host disease (aGVHD) is 1 of the main major complications of post-hematopoietic stem cell transplantation (HSCT). Identifying patients at risk of severe aGVHD may lead to earlier intervention and treatment, resulting in increased survival and a better quality of life. We aimed to identify biomarkers in donor grafts and patient plasma around the time of transplantation that might be predictive of aGVHD development. We build on our previously published methods by using multiplex assays and multicolor flow cytometry. We identified 5 easily assessable cellular markers in donor grafts that combined could potentially be used to calculate risk for severe aGVHD development. Most noteworthy are the T cell subsets expressing IL-7 receptor-a (CD127) and PD-1. Additionally, we identified a potential role for elevated tumor necrosis factor-a levels in both graft and patient before HSCT in development of aGVHD.
43.	Svenberg, Petter, et al. (författare) The importance of graft cell composition in outcome after allogeneic stem cell transplantation in patients with malignant disease 2019 Ingår i: Clinical Transplantation. - : Wiley. - 0902-0063 .- 1399-0012. ; 33:6 Tidskriftsartikel (refereegranskat)abstract Background Graft-versus-host disease (GVHD) and relapse remain majobstacles ftreatment success in allogeneic hematopoietic stem cell transplantation (HSCT). In the present study, we evaluated the immune cell profile of the graft to outcome after HSCT.Study design and method Flow cytometry data of graft cell subsets [CD34+, CD3+, CD19+, CD4+, CD8+, CD3-CD56+CD16+, CD4+CD127lowCD25high] from G-CSF primed peripheral blood stem cell (PBSC) donors was collected retrospectively from 299 patients with hematological malignancies undergoing HSCT between 2006 and 2013. The association to overall survival, transplant-related mortality (TRM), GVHD and probability of relapse was analyzed. Patients outcome from HLA-identical sibling (Sib) (n = 97) and unrelated donors (URD) (n = 202) were analyzed separately as all URD patients received anti-thymocyte globulin (ATG).Results Five-year overall survival was similar in the two cohorts (68% (Sib) vs 65% (URD)). The relapse incidence was significantly lower in the Sib cohort (24% vs 35%, P = 0.04). Multivariate analysis in the URD group revealed an association between a higher CD8+ dose and less relapse (HR, 0.94; 95%CI, 0.90-0.98; P = 0.006) as well as an association between higher CD34+ dose and both higher TRM (HR, 1.09; 95%CI, 1.02-1.20; P = 0.02) and relapse (HR, 1.09; 95%CI, 1.01-1.17; P = 0.025). The Sib analysis showed an association between a higher graft CD19+ dose and more severe acute GVHD (HR, 1,09; 95%CI, 1.03-1.15; P = 0.003) and TRM (HR, 1.09; 95%CI, 1.01-1.17; P = 0.036). In addition, a higher CD4+ graft content was associated to an increased risk for chronic GVHD (HR, 1.02; 95%CI 1.00-1.04; P = 0.06).Conclusion These data indicate an importance of PBSC dongraft composition in patients with a hematological malignancy.
44.	Tauriainen, Johanna, et al. (författare) Single-cell characterization of in vitro migration and interaction dynamics of T cells expanded with IL-2 and IL-7 2015 Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 6 Tidskriftsartikel (refereegranskat)abstract T cells are pivotal in the immune defense against cancers and infectious agents. To mount an effector response against cancer cells, T cells need to migrate to the cancer-site, engage in contacts with cancer cells, and perform their effector functions. Adoptive T cell therapy is an effective strategy as treatment of complications such as relapse or opportunistic infections after hematopoietic stem cell transplantations. This requires a sufficient amount of cells that are able to expand and respond to tumor or viral antigens. The cytokines interleukin (IL)-2 and IL-7 drive T cell differentiation, proliferation, and survival and are commonly used to expand T cells ex vivo. Here, we have used microchip-based live-cell imaging to follow the migration of individual T cells, their interactions with allogeneic monocytes, cell division, and apoptosis for extended periods of time; something that cannot be achieved by commonly used methods. Our data indicate that cells grown in IL-7 + IL-2 had similar migration and contact dynamics as cells grown in IL-2 alone. However, the addition of IL-7 decreased cell death creating a more viable cell population, which should be beneficial when preparing cells for immunotherapy.
45.	Tynngård, Nahreen, 1976-, et al. (författare) Cryopreservation of buffy coat derived platelets: Paired in vitro characterization using uncontrolled versus controlled freezing rate protocols 2021 Ingår i: Transfusion. - : WILEY. - 0041-1132 .- 1537-2995. ; 61:2, s. 546-556 Tidskriftsartikel (refereegranskat)abstract Background Cryopreserved platelets show a reduced recovery and viability after freezing and thawing including several ultrastructural and phenotypic deteriorations compared with liquid-stored platelets. It is suggested that using Controlled-Rate Freezing (CRF) can reduce variability and optimize the functionality profile for cells. The objective of the study is to compare cellular, metabolic, phenotypic and functional effects on platelets after cryopreservation using different freezing rate protocols. Study Design and Methods To evaluate the possible effects of different freezing rate protocols a two-experimental study comparing diverse combinations was tested with a pool and split design. Uncontrolled freezing of platelets in materials with different thermal conductivity (metal vs cardboard) was evaluated in experiment 1. Experiment 2 evaluated uncontrolled vs a controlled-rate freezing protocol in metal boxes. All variables were assessed pre and post cryopreservation. Results Directly after thawing, no major differences in platelet recovery, LDH, ATP, Delta psi, CD62P, CD42b, platelet endothelial cell adhesion molecule and sCD40L were seen between units frozen with different thermal conductivity for temperature. In contrast, we observed signs of increased activation after freezing using the CRF protocol, reflected by increased cell surface expression of CD62P, PAC-1 binding and increased concentration of LDH. Agonist induced expression of a conformational epitope on the GPIIb/IIIa complex and contribution to blood coagulation in an experimental rotational thromboelastometry setup were not statistically different between the groups. Conclusion The use of a uncontrolled freezing rate protocol is feasible, creating a platelet product comparable to using a controlled rate freezing equipment during cryopreservation of platelets.
46.	Tynngård, Nahreen, 1976-, et al. (författare) Haemostatic responsiveness and release of biological response modifiers following cryopreservation of platelets treated with amotosalen and ultraviolet A light 2020 Ingår i: Blood Transfusion. - : SIMTIPRO SRL. - 1723-2007. ; 18:3, s. 191-199 Tidskriftsartikel (refereegranskat)abstract Background - Due to the risk of replication of contaminating pathogens, platelets have a limited storage time of 5 days, which can be prolonged to 7 days by the use of pathogen inactivation technologies. Cryopreservation (CP) may be an alternative to permit longer storage periods and increased availability. However, the preparation of platelets can result in secretion of biological response modifiers (BRM), which can cause adverse transfusion reactions in the recipient. We investigated the impact of CP on platelet function and release of BRM in untreated (conventional) and pathogen-inactivated (PI) platelet concentrates. Materials and methods - Twelve buffy coat-derived platelet units were treated with amotosalen and ultraviolet A light to inactivate pathogens. Twelve untreated units were used as controls. The 24 units were cryopreserved and in vitro variables were analysed before and after CP. The in vitro variables investigated included platelet surface receptors and activation markers by flow cytometry, and coagulation time by viscoelastography. A panel of BRM, including cytokines, was investigated. Results - CP of both conventional and PI platelets resulted in a significant increase of BRM with similar increases of most of the BRM after CP of conventional and PI platelet concentrates. The increase in some of the BRM correlated significantly with shortened coagulation time, increased P-selectin expression, reduced mitochondrial transmembrane potential, and reduced capacity to respond to stimulation with ADP and collagen. Discussion - Cryopreservation of both conventional and PI platelets results in secretion of BRM. The increase in some of the BRM correlated with changes in platelet function variables and suggests that BRM release is affected, in part, in a similar way by CP as are changes in platelet function variables. PI with amotosalen and ultraviolet A light in combination with CP did not affect the release of immunomodulatory factors more than CP alone did.
47.	Törlén, J., et al. (författare) Effect of Graft-versus-Host Disease Prophylaxis Regimens on T and B Cell Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation 2019 Ingår i: Biology of blood and marrow transplantation. - : Elsevier. - 1083-8791 .- 1523-6536. ; 25:6, s. 1260-1268 Tidskriftsartikel (refereegranskat)abstract Lymphocyte reconstitution is pivotal for successful long-term outcome after allogeneic hematopoietic stem cell transplantation (HSCT), and conditioning regimen and post-transplantation immunosuppression are risk factors for prolonged immunodeficiency. Nevertheless, the effects of different immunosuppressive protocols on lymphocyte output and replicative capacity have not been investigated. Here we assessed T cell receptor excision circles (TREC), kappa-deleting recombination excision circles (KREC), and T cell telomere length (TL) as proxy markers for immune reconstitution in patients in a prospective randomized trial comparing graft-versus-host disease (GVHD) prophylaxis after transplantation (cyclosporine/methotrexate versus tacrolimus/sirolimus; n = 200). Results showed that medians of TREC, KREC, and TL were not significantly different between the prophylaxis groups at any assessment time point during follow-up (24 months), but the kinetics of TREC, KREC, and TL were significantly influenced by other transplantation-related factors. Older recipient age, the use of antithymocyte globulin before graft infusion, and use of peripheral blood stem cell grafts were associated with lower TREC levels, whereas acute GVHD transiently affected KREC levels. Patients with lymphocyte excision circle levels above the median at ≤6 months post-transplantation had reduced transplantation-related mortality and superior 5-year overall survival (P <.05). We noticed significant T cell telomere shortening in the patient population as a whole during follow-up. Our results suggest that lymphocyte reconstitution after transplantation is not altered by different immunosuppressive protocols. This study has been registered at ClinicalTrials.gov (identifier: NCT00993343).
48.	Uhlin, Anders, et al. (författare) Perceptions of Democracy Among Local Elites: A Comparative Study of Five Russian Regions 2005 Ingår i: The Challenge of the Baltic Sea Region. Culture, Ecosystems, Democracy. ; , s. 285-306 Bokkapitel (övrigt vetenskapligt/konstnärligt)
49.	Uhlin, Michael, et al. (författare) Mesenchymal Stem Cells Inhibit Thymic Reconstitution After Allogeneic Cord Blood Transplantation 2012 Ingår i: Stem Cells and Development. - : Mary Ann Liebert Inc. - 1547-3287 .- 1557-8534. ; 21:9, s. 1409-1417 Tidskriftsartikel (refereegranskat)abstract Cord blood (CB) as a source of stem cells has been a successful addition to the field of allogeneic stem cell transplantation (ASCT). The increased human leukocyte antigen (HLA) permissiveness of CB grafts has made it possible for more patients to undergo treatment. The drawback is that patients suffer from a longer period of compromised immunity. We analyzed T-cell receptor excision circles (TRECs), immunoglobulin G (IgG), and immunoglobulin M (IgM) levels after cord blood transplantation (CBT) in 50 patients transplanted at our center. These immunological parameters were compared retrospectively with clinical factors and complications. We found that TREC levels after CBT were lower in adults, patients with myeloablative conditioning, and in patients with a lower nucleated cell dose in the graft. In addition mesenchymal stem cells (MSC) as co-infusion at the time of CBT had a negative effect on TREC reconstitution. This was found to be associated with decreased overall survival for this patient category. Reduced IgM and IgG levels post-CBT were associated with a major ABO mismatch, and infusion of MSCs. Our results highlight the importance of close monitoring of the immune reconstitution after CBT. In addition it shows a potentially new suppressive effect of MSCs on the immune system.
50.	Uhlin, Michael (författare) Regulation of non-responsiveness and death in cytotoxic T cells by the agonistic potency of MHC : peptide ligands 2006 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract CD8+ T lymphocytes are important for immunological control of infections and tumors. The key interaction required to initiate the process of T cell activation is the engagement of the T cell receptor (TCR) with a major histocompatibility complex (MHC) class I/peptide complex on an antigen presenting cell (APC). Depending on the affinity of the interaction between the TCR and MHC class I molecule, different arrays of signaling pathways can be activated in the T cell. Molecular alterations in the peptide bound to the MHC class I can lead to a lower affinity of the MHCTCR-interaction resulting in incomplete or qualitatively different T-cell responses. Altered peptide ligands (APLs) exhibiting such activity are referred to as partial agonists and often occur naturally through genetic instability, which affects T cell epitopes derived from rapidly mutating viruses or tumor-associated cellular antigens. We studied the molecular basis of partial agonism using MHC class I/peptide tetramer complexes. By using tetramers assembled with a fully agonist peptide or its synthetic variant we could study the relationship between tetramer staining, cytokine production and different pathways of activation induced cell death (AICD). We found that positive tetramer staining correlated with at least two different activation programs in CD8+ T lymphocytes: full scale activation associated with Fas-dependent AICD and an incomplete activation followed by Fas-independent AICD. Further, we used raft-disrupting agents to assess the role of lipid rafts in determining the agonistic potency of different peptide ligands. We showed that overall binding of specific tetramers to CTLs was reduced upon raft disruption, although the half-life of tetramer:TCR complexes formed under these conditions was not affected. These findings suggest that different TCR complexes on the surface of CTLs may have different requirements for cholesterol and CTLs may be heterogeneous in their raft structure. In addition we analyzed programs of negative regulation of CD8+ T lymphocytes and the capacity of APLs to activate and modulate such programs. Upon specific triggering CD8+ T-cells become refractory to a secondary stimulus; a condition referred to Activation induced Non-Responsiveness (AINR). We have shown that TCR-triggering results in a novel degradation pathway of Lck, a kinase which plays a critical role in the initiation of T cell activation. Down-regulation of Lck through degradation correlated with AINR in CTLs. By blocking Lck degradation we could prevent the development of AINR. We further investigated how activation of CTLs with APLs affected Lck expression. The capacity of different peptide variants to induce Lck degradation correlated with their agonistic potency. Inefficient recognition of APLs by specific T lymphocytes is believed to contribute to the failure of the immune system to control certain tumor types and progressive viral diseases. To better understand the regulation of APL, activity by immunologic help, we analyzed the capacity of exogenous IL-2 and IL-15 to influence different aspects of activation triggered in CTLs by either fully or partially agonistic peptide ligands. We showed that signals induced by the lymphokines synergize with weak TCR signaling induced by partially agonistic APL, converting many of these peptides from inhibitory to stimulatory ligands. We also demonstrated that IL-2 and IL-15 suppress induction of a death receptor-independent apoptotic program triggered by partially agonistic APL. In conclusion, we have analyzed the molecular basis of partial agonism in CTL recognition of peptide epitopes and characterized molecular changes associated with death and AINR in specific CTLs. We have shown that structural changes in the sequence of CTL peptide epitopes may decrease the affinity of MHC/TCR interactions and generate APLs, which not only trigger incomplete activation programs but also induce and modulate negative regulation programs in CTLs. This APL induced signaling of suppressive nature appears to be more prominent in the absence of immunological help, suggesting that under conditions of immune deregulation APLs may actively suppress CTL responses against infectious agents or tumors.

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