| 1. |
- Svenvik, M, et al.
(författare)
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Increased IFN-? response to transplantation antigens measured by cytokine MLC : Indications for a bi-phasic response pattern
- 2003
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Ingår i: Transplant Immunology. - 0966-3274 .- 1878-5492. ; 11:1, s. 101-105
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Tidskriftsartikel (refereegranskat)abstract
- The immunological reactivity to major histocompatibility transplantation antigens (MHC) is important in clinical manifestations such as graft rejection and graft-vs.-host disease. To evaluate the allogeneic cytokine response pattern we used a newly developed cytokine mixed leukocyte culture (MLC) technique. Blood mononuclear cells from healthy women (n=6) were exposed to cells from another person and to pooled cells from 28 blood donors (MHC-pool). The secretion kinetics of IL-4 and IFN-? from the responder cells was analysed by ELISPOT. We found a higher IFN-? response to the MHC-pool compared with the IL-4 secretion. Both the total secretion of IFN-? for 7 days and the median value of IFN-? in each individual was increased compared with IL-4. The IFN-? response showed a bi-phasic pattern with the major peak on day 6-7. Our results indicate that allo-responses are mainly Thl-like responses, displaying a bi-phasic pattern. This knowledge may be useful, and the methods suitable, in the studies of allo-responses in transplantation and pregnancy.
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| 2. |
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| 3. |
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| 4. |
- Berglund, David, et al.
(författare)
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Imaging the in vivo fate of human T cells following transplantation in immunoincompetent mice - Implications for clinical cell therapy trials
- 2013
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Ingår i: Transplant Immunology. - : Elsevier BV. - 0966-3274 .- 1878-5492. ; 29:1-4, s. 105-108
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Tidskriftsartikel (refereegranskat)abstract
- Many forms of adoptive T cell therapy are on the verge of being translated to the clinic. To gain further insight in their immunomodulating functions and to optimize future clinical trials it is essential to develop techniques to study their homing capacity. CD4+ T cells were labeled using [In-111]oxine, and the radioactive uptake was determined in vitro before intravenous injection in immunodeficient mice. In vivo biodistribution of [In-111] oxine-labeled cells or tracer alone was subsequently measured by mu SPECT/CT and organ distribution. CD4+ T cells incorporated [In-111]oxine with higher labeling yield using Ringer-Acetate compared to 0.9% NaCl. Cellular viability after labeling with [In-111]oxine was not compromised using less than 0.4 MBq/million cells. After intravenous infusion CD4+ T cells preferentially homed to the liver (p < 0.01) and spleen (p < 0.05). This study presents a protocol for labeling of T cells by [In-111]oxine with preserved viability and in vivo tracking by SPECT for up to 8 days, which can easily be translated to clinical cell therapy trials.
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| 5. |
- Berglund, David, et al.
(författare)
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Isolation, expansion and functional assessment of CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients awaiting kidney transplantation
- 2012
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Ingår i: Transplant Immunology. - : Elsevier BV. - 0966-3274 .- 1878-5492. ; 26:1, s. 27-33
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Tidskriftsartikel (refereegranskat)abstract
- Background: The immunosuppressive properties of regulatory T cells have emerged as an attractive tool for the development of immunotherapies in various disease contexts, e.g. to treat transplantation induced immune reactions. This paper focuses on the process of obtaining and functionally characterizing CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients awaiting kidney transplantation. Methods: From October 2010 to March 2011 uremic patients awaiting living donor kidney transplantation, and their corresponding kidney donors, were enrolled in the study. A total of seven pairs were included. Isolation of CD4+CD25+FoxP3+ regulatory T cells was performed by magnetic activated cell sorting of peripheral blood mononuclear cells obtained from the uremic patients. Donor specific Tr1 cells were differentiated by repetitive stimulation of immature CD4+ T cells with immature dendritic cells, with the T cells coming from the future kidney recipients and the dendritic cells from the corresponding kidney donors. Cells were then expanded and functionally characterized by the one-way mixed leukocyte reaction and assessment of IL-10 production. Phenotypic analysis was performed by flow cytometry. Results: The fraction of CD4+CD25+FoxP3+ regulatory T cells after expansion varied from 39.1 to 50.4% and the cells retained their ability to substantially suppress the mixed leukocyte reaction in all but one patient (3.8–19.2% of the baseline stimulated leukocyte activity, p<0.05). Tr1 cells were successfully differentiated from all but one patient and produced high levels of IL-10 when stimulated with immature dendritic cells (1,275–11,038% of the baseline IL-10 secretion, pb0.05). Conclusion: It is practically feasible to obtain and subsequently expand CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients without loss of function as assessed by in vitro analyses. This forms a base for adoptive regulatory T cell therapy in the setting of living donor kidney transplantation.
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| 6. |
- Berglund, David, et al.
(författare)
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Screening of mortality in transplant patients using an assay for immune function
- 2011
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Ingår i: Transplant Immunology. - : Elsevier BV. - 0966-3274 .- 1878-5492. ; 24:4, s. 246-250
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: So far, the ImmuKnow Immune Cell Function Assay (Cylex, Inc., Columbia, MD, USA) has been used to assess risks of infection and rejection in transplant patients. We hypothesized that the ImmuKnow assay might be used for mortality screening in transplant patients overall. METHODS: In the period of February 2007 to December 2009, at the Uppsala University Hospital, 362 patients who received either kidney, kidney+pancreas, kidney+islet cells, liver or liver+kidney allografts were randomly screened using the ImmuKnow assay. All causes of mortality were compared between two groups: patients with at least one ImmuKnow assay below 175ng/mL and patients with all ImmuKnow assays from 175ng/mL and above. Subsequently, the frequency of rejection within thirty days of the ImmuKnow assay was compared between these two groups. RESULTS: The study included 1031 ImmuKnow assays obtained from the 362 patients. A total of 111 patients had at least one ImmuKnow below 175ng/mL and 251 patients had all their ImmuKnow assays from 175ng/mL and above. By January 31st 2010, 16 of 111 patients (14.4%) with at least one ImmuKnow assay below 175ng/mL were deceased, compared to 13 of 251 patients (5.2%) with all ImmuKnow assays from 175ng/mL and above (p=0.0053, Fisher's exact test). There was no difference in the frequency of rejection between the two groups (19.8% versus 17.5%, p=0.66). CONCLUSIONS: In addition to assessing relative risks of infection and rejection in transplant patients, the ImmuKnow assay may be used to identify patients with increased risk of short-term mortality. Transplant patients being highly overimmunosuppressed as assessed by the ImmuKnow assay do not seem to have a lower risk of short-term rejection.
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| 7. |
- Chen, Jibing, et al.
(författare)
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An N-(alkylcarbonyl)anthranilic acid derivative prolongs cardiac allograft survival synergistically with cyclosporine A in a high-responder rat model
- 2010
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Ingår i: Transplant Immunology. - : Elsevier BV. - 1878-5492 .- 0966-3274. ; 23:4, s. 180-184
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the immunosuppressive effects of the dihydroortate dehydrogenase (DHODH) inhibitor compounds ABR-222417 and ABR-224050 from Active Biotech (Sweden). We verified the inhibitory effects of these compounds on the proliferation of CD4(+) and CD8(+) T-cells in vivo by using superantigen staphylococcus enterotoxin A (SEA)-mediated proliferation test. To evaluate their efficacy, the compounds were screened in a low-responder heart allograft transplantation model in rats [heart from Piebald Virol Glaxo (PVG) transplanted to Dark Agouti (DA)]. The immunosuppressive effects of the compounds were then investigated in a high-responder model (DA to PVG). Treatment with ABR-222417 (30 mg/kg) was more efficient than that with ABR-224050 (10 mg/kg), and the former provided a longer graft median survival time (MST, 29.5 days) than the latter (MST, 18.5 days). Furthermore, there was a marked increase in graft survival time (53 days) when low doses of ABR-222417 and cyclosporine A (CsA) were used in combination. No sign of tolerability problems was detected using this combination or when ABR-222417 was used singly at a higher dose. Furthermore, T-cell proliferation studies in vitro support that the anti proliferative effect of ABR-222417 is caused by inhibition of de novo pyrimidine synthesis, which is the consequence of DHODH inhibition. These results show that ABR-222417 had marked immunosuppressive effects on the heart allograft transplantation and that it exerts an even more powerful inhibitory effect on graft rejection when used in combination with CsA, with good tolerability. (C) 2010 Elsevier B.V. All rights reserved.
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| 8. |
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| 9. |
- Dai, Helong, et al.
(författare)
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Blockade of CD27/CD70 pathway to reduce the generation of memory T cells and markedly prolong the survival of heart allografts in presensitized mice
- 2011
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Ingår i: Transplant Immunology. - : Elsevier BV. - 1878-5492 .- 0966-3274. ; 24:4, s. 195-202
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alloreactive memory T cells are a major obstacle to transplantation acceptance due to their capacity for accelerated rejection. Methods: C57BL/6 mice that had rejected BALB/c skin grafts 4 weeks earlier were used as recipients. The recipient mice were treated with anti-CD154/LFA-1 with or without anti-CD70 during the primary skin transplantation and anti-CD154/LFA-1 or not during the secondary transplantation of BALB/c heart. We evaluated the impact of combinations of antibody-mediated blockade on the generation of memory T cells and graft survival after fully MHC-mismatched transplantations. Results: One month after the primary skin transplantation, the proportions of CD4(+) memory T cells/CD4(+) T cells and CD8(+)memory T cells/CD8(+) T cells in the anti-CD154/LFA-1 combination group were 47.32 +/- 428% and 23.18 +/- 2.77%, respectively. In the group that included anti-CD70 treatment, the proportions were reduced to 34.10 +/- 2.71% and 12.19 +/- 3.52% (P<0.05 when comparing the proportion of memory T cells between the two groups). The addition of anti-CD70 to the treatment regimen prolonged the mean survival time following secondary heart transplantation from 10 days to more than 90 days (P<0.001). Furthermore, allogenic proliferation of recipient splenic T cells and graft-infiltrating lymphocytes were significantly decreased. Meanwhile, the proportion of regulatory T cells was increased to 9.46 +/- 1.48% on day 100 post-transplantation (P<0.05). Conclusions: The addition of anti-CD70 to the anti-CD154/LFA-1 combination given during the primary transplantation reduced the generation of memory T cells. This therapy regimen provided a potential means to alleviate the accelerated rejection mediated by memory T cells during secondary heart transplantation and markedly prolong the survival of heart allografts. (C) 2011 Elsevier B.V. All rights reserved.
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| 10. |
- Engstrand, Mats, et al.
(författare)
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Lymphocyte propagation from biopsies of kidney allografts
- 2006
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Ingår i: Transplant Immunology. - : Elsevier BV. - 0966-3274 .- 1878-5492. ; 16:3-4, s. 215-219
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Tidskriftsartikel (refereegranskat)abstract
- Morphological evaluation of transplant biopsies, usually using the Banff classification, is the most important tool to diagnose rejection after kidney transplantation. However, morphological analysis only scores the amount and localisation of infiltrating cells, and studies show that up to 30% of grafts with a stable function display infiltration of lymphocytes consistent with acute cellular rejection. Methods to study the functional properties of the infiltrating lymphocytes are therefore needed. We applied a tissue culture system on biopsies from transplanted human kidneys, allowing infiltrating cells to propagate out from the tissue. Cells were then counted and subtyped by flow cytometry. The results were correlated to morphology. In total, 92 biopsies from 69 patients were analysed. For 14 patients, serial biopsies were available. In grafts with cellular or combined cellular and vascular rejection, the number of ex vivo propagated mononuclear cells was higher than from non-rejecting grafts. A similar pattern was seen for CD3(+) T cells as well as for T cells expressing CD25 or MHC class II antigens. However, the proportion of CD25(+) or MHC class II(+) T lymphocytes was similar in all groups (no rejection, vascular rejection, borderline changes, cellular rejection, combined cellular and vascular rejection). In all groups the number of CD4(+) cells was higher than the number of CD8(+) cells. The results confirm previous experimental studies showing that graft-infiltrating cells are possible to culture in vitro and that lymphocyte propagation correlates to acute cellular rejection. Tissue culturing is easy to perform and evaluate and can be used to determine and analyse the cellular immune response to allografts and may thus be used as a complement to morphological analyses.
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| 11. |
- Ivanics, Tommy, et al.
(författare)
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Experience with solid organ transplantation in patients with previous immunotherapy treatment is still limited but this is changing : The survey-based view of the global transplant society
- 2022
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Ingår i: Transplant Immunology. - : Elsevier. - 0966-3274 .- 1878-5492. ; 73
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Tidskriftsartikel (refereegranskat)abstract
- Background: The use of immunotherapy for cancer is increasing and is expected to continue growing. The outcomes after solid organ transplantation(SOT) in patients who received immunotherapy before SOT remain unclear. We evaluated the global transplant surgery community's attitude towards and experience with patients who received immunotherapy for malignancy before SOT. Methods: An online-based survey was sent to North American transplant program directors in December-2020 and members of the International Liver Transplant Society in November-2021 evaluating experiences with and attitudes towards SOT in recipients with previous immunotherapy for cancer. Results: A total of 119 respondents completed the survey(119/175;completion rate:68%), representing centers from North America, South America, Europe, Asia, and Australia. Seventy-one(62%) respondents would consider SOT in patients with a previous history of immunotherapy for cancer, whereas thirty-nine(34%) were aware of such immunotherapy-treated recipients being transplanted, with an increasing trend over the last few years(2016 [n = 1]-2020[n = 14]). Institutional clinical management policies in this setting were lacking in most centers(n = 85[75%]). Conclusions: The international transplant community is receptive to transplanting transplant candidates previously treated with immunotherapy for cancer, although experience is still limited. In this context, more centers have started to offer SOT to patients with a history of immunotherapy for cancer in recent years. However, support from clear and robust institutional policies in this endeavor is scant. Therefore, there is a high need for consensus guidelines to inform future clinical management, especially as immunotherapy for cancer is likely to continue to increase in the coming years.
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| 12. |
- Johnsson, Cecilia, et al.
(författare)
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Phenotyping of ex vivo propagated graft-infiltrating cells-a tool to monitor rejection in the early post-operative period
- 2006
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Ingår i: Transplant Immunology. - : Elsevier BV. - 0966-3274 .- 1878-5492. ; 16:2, s. 81-87
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Tidskriftsartikel (refereegranskat)abstract
- Objective and fast methods to diagnose rejection after organ transplantation are needed. In the present study, the ex vivo propagation technique was evaluated for its ability to detect rejection at two different time-points after experimental heart transplantation. Syngeneic and allogeneic heterotopic heart transplantations were performed using inbred rat strains. After 6 or 15 days, cardiac graft biopsies were put in culture and infiltrating cells isolated by the ex vivo propagation technique. The isolated cells were counted and phenotyped by flow cytometry. In parallel, graft sections were analysed with regard to morphology and the presence of infiltrating cells as determined by immunohistochemical stainings. On day 15 after transplantation, the number of cells possible to isolate through ex vivo propagation reflected the morphological changes of the graft, i.e. considerably more cells were obtained from allogeneic transplants undergoing rejection (1052 +/- 205) than from allogeneic grafts under cyclosporine protection (513 +/- 135; p<0.05) or from syngeneic grafts (378 +/- 87; p<0.01). Six days after transplantation the allogeneic grafts were strongly rejected with massive cellular infiltration, still there was no difference between allogeneic and syngeneic grafts as to the number of ex vivo propagated cells. However, the proportion of IL-2-receptor expressing T lymphocytes was increased (15.4 +/- 1.8% vs. 9.5 +/- 1.4%; p < 0.05) and the CD4/CD8 ratio reduced (1.0 +/- 0.1 vs. 2.8 +/- 0.2; p < 0. 001) in the allogeneic group as compared with the syngeneic. We conclude that the ex vivo propagation technique can be used to distinguish rejection from non-rejection both early and later after transplantation, provided that not just cell counting but also phenotyping of the graft-infiltrating cells is performed.
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| 13. |
- Kang, Xiangpeng, et al.
(författare)
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Isatis tinctoria L. combined with co-stimulatory molecules blockade prolongs survival of cardiac allografts in alloantigen-primed mice
- 2010
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Ingår i: Transplant Immunology. - : Elsevier BV. - 1878-5492 .- 0966-3274. ; 23:1-2, s. 34-39
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Tidskriftsartikel (refereegranskat)abstract
- Memory T cells present a unique challenge in transplantation. Although memory T cells express robust immune responses to invading pathogens. they may be resistant to the effects of immunosuppressive therapies used to prolong graft survival. In previous studies, we found that compound K. the synthesized analogue of highly unsaturated fatty acids from Isatis tinctoria L., reduced acute cardiac allograft rejection in mice (Wang et al., 2009 [1]). Here, we further investigated the effect of compound K on cardiac allograft rejection in alloantigen-primed mice. We found that compound K significantly inhibited CD4(+) and CD8(+) memory T cells proliferation in a mixed lymphocyte reaction (MLR). In vivo, compound K combined with anti-CD154 and anti-LFA-1 monoclonal antibodies (mAbs) significantly extended the survival time of heart grafts in alloantigen-primed mice with no obvious toxic side effects. Furthermore, our data suggests that compound K works by reducing the expression of both IL-2 and IFN-gamma within the graft rather than enhancing expression of regulatory T cells (Tregs). Compound K can also inhibit the alloresponses of memory T cells, while increasing the proportion of CD4(+) memory T cells in the spleen of the recipients and significantly reducing the level of alloantibodies in the serum. Our study highlights the unique immune effects of compound K that may be further explored for clinical use in extending the survival of transplant grafts. (C) 2010 Elsevier B.V. All rights reserved.
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| 14. |
- Lin, Yingying, et al.
(författare)
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Arsenic trioxide is a novel agent for combination therapy to prolong heart allograft survival in allo-primed T cells transferred mice
- 2011
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Ingår i: Transplant Immunology. - : Elsevier BV. - 1878-5492 .- 0966-3274. ; 25:4, s. 194-201
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Tidskriftsartikel (refereegranskat)abstract
- Alloreactive memory T cells are major barriers to transplantation acceptance due to their capacity to accelerate rejection. Here, we investigated the effects of combined treatment with arsenic trioxide (As(2)O(3)) and blocking monoclonal antibodies (mAb) against CD154 and LFA-1 (anti-CD154/LFA-1) on graft survival as well as changes in pathology and immunological responses in mice with adoptively transferred allo-primed T cells. The mean survival time (MST) for the cardiac allografts in recipient mice receiving the combination of As(2)O(3) and anti-CD154/LFA-1 was significantly longer (>113.7 days) compared to those receiving anti-CD154/LFA-1 (232 days), As(2)O(3) (12.5 days) alone or no treatment (5.5 days). This combined strategy distinctly inhibited lymphocyte infiltration in grafts, proliferation of splenic T cells and the generation of memory T cells in spleens. Moreover, the combined treatment caused the significant down-regulation of IL-2 and IFN-gamma accompanied by increased expression of TGF-beta and regulatory T cells (Tregs) in spleens, which led to long-term cardiac allograft survival in recipient mice. These results highlight the potential application of As(2)O(3) and its contribution in combination therapy with antibody blockade to delay rejection by memory T cells. (C) 2011 Elsevier B.V. All rights reserved.
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| 15. |
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| 16. |
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| 17. |
- Runstrom, Anna, et al.
(författare)
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IgM single antigen bead HLA-assay is affected by imlifidase through the cleavage of IgG but not IgM
- 2021
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Ingår i: Transplant Immunology. - : Elsevier. - 0966-3274 .- 1878-5492. ; 68
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The aim of this study was to investigate if human IgM is a cleavable substrate for imlifidase and to explain an observed effect in anti-HLA IgM single antigen bead (SAB) assays in sensitized patients. Methods: Serum samples collected pre-and 24 h post-imlifidase administration from sensitized patients enrolled in a phase II trial were investigated for anti-HLA IgG and IgM using SAB assays, with and without in vitro IgG depletion using a CaptureSelectTM affinity matrix. In addition, pre-dose samples and purified human IgM samples were treated with imlifidase in vitro and evaluated by SDS-PAGE, Western blot (PE-conjugated anti-human IgM) and SAB (IgG, IgM) assays. Results: By comparing the mean fluorescence intensity (MFI) of HLA-beads, pre-and post-imlifidase administration, three IgM-related patterns were observed; IgM-specific HLA-SABs with an increased MFI post-imlifidase, IgM-specific HLA-SABs with a decreased MFI post-imlifidase, and IgM-specific HLA-SABs with a marginal MFI difference between the pre-and post-imlifidase administration. These IgM signal patterns were observed despite neither purified IgM nor serum IgM could be cleaved by imlifidase. After removing IgG, the effects observed on anti-HLA IgM was largely eliminated with the biggest differences seen in patients with very high anti-HLA IgG in pre-dose samples. Conclusion: We demonstrate that imlifidase does not cleave human IgM, including HLA-specific IgM antibodies from highly sensitized subjects. Observed decreases of SAB-HLA IgM signals after imlifidase treatment may result from the cleavage of IgG-IgM complexes which are bound to SAB-HLA. Serum analysis of patients with high levels of anti-HLA IgG will result in a more accurate SAB-HLA IgM reading after IgG depletion.
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| 18. |
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| 19. |
- Stenbäck, Anders, et al.
(författare)
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T-cell inhibition does not aggravate bacterial translocation from rat small bowel
- 2006
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Ingår i: Transplant Immunology. - : Elsevier BV. - 0966-3274 .- 1878-5492. ; 16:3-4, s. 208-214
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Tidskriftsartikel (refereegranskat)abstract
- Background: T-cell mediated immunity has been proposed to have an important function in the defence against translocating microbes from the gastrointestinal tract. After small bowel transplantation massive T-cell immunosuppression is necessary to avoid rejection. As a consequence, infections with intestinal bacteria are the main contributors to mortality in this setting. This could further imply that T cells are important in limiting bacterial translocation. In a model for bacterial translocation from small bowel in the rat we examined the outcome of T-cell inactivation. Methods: The studies were performed in a model of bacterial translocation from a Thiry-Vella loop of small bowel in the rat. The animals were treated with an anti-α/β T-cell receptor monoclonal antibody (R73). Inhibition of T-cell activation was also made using the immunosuppressive drug cyclosporin A. All animals were sacrificed on day 3 postoperatively and translocation to the mesenteric lymph nodes, liver, spleen, lung and blood was evaluated. Results: Treatment with R73 resulted in an almost complete labelling of T cells but did not result in any increased bacterial translocation compared to animals treated with saline. Neither did immunosuppression with cyclosporin A. Conclusions: In the model of bacterial translocation from a defunctionalised loop of small bowel the inhibition of T cells does not increase bacterial translocation to mesenteric lymph nodes or promote the systemic spread of the translocating bacteria. This indicates that T cells do not have any important protective function against translocating microbes from defunctionalised small bowel.
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| 20. |
- Thorvaldson, Lina, et al.
(författare)
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Factors influencing the regulation of cytokine balance during islet transplantation in mice
- 2009
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Ingår i: Transplant Immunology. - : Elsevier BV. - 0966-3274 .- 1878-5492. ; 20:3, s. 186-194
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Tidskriftsartikel (refereegranskat)abstract
- Many experimental islet studies compare the effect of allogeneic transplantations with either syngeneically transplanted or sham-operated animals. Presently we examined multiple "control" treatments to be able to distinguish effects by the operating procedures themselves versus reactions induced by islet graft rejection. Herein, we have studied untreated, sham-operated, syngeneically or allogeneically (C57BL/6) islet transplanted BALB/c mice, and subsequently examined cytokine production (TNFalpha, IFNgamma, IL-4, IL-10, IL-17 and TGF-beta) in vitro by RT-PCR and ELISA in spleen cells and transplants. To investigate if the strain of the recipient mice influences cytokine production we also performed allogeneic islet transplantations in the reverse direction. So-called control treatments such as sham operations and syngeneic transplantations had a distinct effect on cytokines in spleen cells, possibly induced by surgery and/or anaesthesia. This seems to decrease the regulatory T cells, thereby leading to increased cytokine expression. Furthermore, spleen cells from surgically manipulated animals seem to have a decreased responsive capacity to con A stimulation in culture. Cytokine generation, FoxP3 mRNA expression and COX-2 mRNA expression in the two investigated mouse strains were sometimes altered in opposite directions by the treatments. In conclusion, the genetic background of both the islet donor and recipient has a major impact on both the magnitude and skewing of a cytokine response. Moreover, factors not directly related to allorejection influences systemic cytokine production in connection to islet transplantation.
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| 21. |
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| 22. |
- Ullah, Kaleem, et al.
(författare)
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Expanding the living liver donor pool in countries having limited deceased donor activity : Pakistani perspective
- 2022
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Ingår i: Transplant Immunology. - : Elsevier. - 0966-3274 .- 1878-5492. ; 75
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Tidskriftsartikel (refereegranskat)abstract
- Over the last decades, liver transplantation (LT) has evolved into a life-saving procedure. Due to limited deceased donor activities in the eastern world, living donor liver transplantation (LDLT) had flourished tremendously in most Asian countries. Yet, these LDLT activities fall short of meeting the expected demands. Pakistan, a developing country, bears a major burden of liver diseases. Currently, only few centers offer LDLT services in the country. On the other hand, deceased donor liver transplantation (DDLT) activities have not started due to social, cultural, and religious beliefs. Various strategies can be adopted successfully to overcome the scarcity of live liver donors (LLDs) and to expand the donor pool, keeping in view donor safety and recipient outcome. These include consideration of LLDs with underlying clinical conditions like G6PD deficiency and Hepatitis B core positivity. Extended donor criteria can also be utilized and relaxation can be made in various donors' parameters including upper age and body mass index after approval from the multidisciplinary board. Also, left lobe grafts, grafts with various anatomical variations, and a low graft-to-recipient ratio can be considered in appropriate situations. ABO-incompatible LT and donor swapping at times may help in expanding the LLDs pool. Similarly, legislation is needed to allow live non-blood-related donors for organ donations. Finally, community education and awareness through various social media flat forms are needed to promote deceased organ donation.
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| 23. |
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| 24. |
- Qi, Zhongquan, et al.
(författare)
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Single dose anti-CD4 monoclonal antibody for induction of tolerance to cardiac allograft in high- and low-responder rat strain combinations
- 1997
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Ingår i: Transplant Immunology. - 0966-3274. ; 5:3, s. 204-211
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Tidskriftsartikel (refereegranskat)abstract
- Repeated administration of monoclonal antibodies (mAb) directed against the CD4 lymphocyte receptor may induce specific, long-lasting unresponsiveness to fully MHC-mismatched cardiac allografts in rats without additional immunosuppression. We assessed the effect of a single dose of murine anti-rat depleting anti-CD4 mAb (OX-38) on allograft survival in high- and low-responder rat strain combinations. Isogenic strains of DA (RT1(av1)), PVG (RT1(c)), AUG (RT1(c)), and WF (RT1(u)) rats were used. Recipients in antibody treated groups were given one dose of 5 mg/kg OX-38 mAb on the day of transplant, a dose which was shown to effectively deplete (or block) circulating CD4+ T cells. Other groups were treated for 10 days with cyclosporin A (CsA) and/or Linomide, a novel immunomodulator, which is the first compound able to fully eliminate the effect of CsA in the rat cardiac allograft model. The DA strain was identified as a low-responder to the allogeneic haplotype RT1(c) (PVG or AUG), but not to RT1(u) (WF), and developed true tolerance following RT1(c) grafting and OX-38 or low-dose CsA (5 mg/kg) induction, as verified by the response to retransplantation of a graft from the same donor strain or a third-party challenge. PVG recipients of DA grafts were characterized by high response and only modest (OX-38; median 9.5 days) or moderate (CsA; 23.5 days) prolongation of graft survival. Contrasting graft survival results were obtained in the low-responder combination, either very early rejection (at 10 days) or permanent graft survival (> 100 days). Linomide challenge affected CsA treatment in the high-responder combination but not tolerance induction in the low-responder combination, or the effect of OX-38. It was concluded that in rat heart transplantation a single-dose anti-CD4 mAb therapy may induce permanent donor-specific unresponsiveness in a low-responder strain combination, and that anti-CD4 mAb seems to be unique among immunosuppressive agents while being resistent to challenge by Linomide.
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| 25. |
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| 26. |
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| 27. |
- Lukes, Daniel J, et al.
(författare)
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Early onset of rejection in concordant hamster xeno hearts display signs of necrosis, but not apoptosis, correlating to the phosphocreatine concentration.
- 2003
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Ingår i: Transplant immunology. - 0966-3274. ; 12:1, s. 29-40
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The importance of apoptosis contra necrosis for ischemia/reperfusion (RP) and acute rejection in concordant rodent xenotransplantation is largely unknown. We explored this question by comparing rodent allo and concordant xenotransplants with different morphological methods to detect apoptosis and biochemical data on the levels of high-energy phosphates obtained with in vitro 31Phosphorous Magnetic Resonance Spectroscopy (31P MRS). More specifically, we applied a hitherto unused method in transplantation research, apoptosis specific biotin labeled oligonucleotides designed with a 10 base pair stem region and a 20 nucleotides large loop that form a hairpin like shape. The results obtained with this method were compared to results obtained with the more widely used in situ 3'-end labeling of DNA (TUNEL) assay and extraction and gel electrophoresis of labeled DNA (DNA laddering). METHODS: Cervical heart transplantations were performed between inbred Lewis (L) (RT1l) to L, L to DA (RT1a) rats, hamster (H) to H and H to L (X) (n=5 for all groups except for X, n=9). All hearts were subjected to 30 min of cold ischemia (+4 degrees C) and 6 h of RP before explantation. In vitro 31P MRS was used to determine the phosphocreatine (PCr), beta-adenosine triphosphate (beta-ATP) concentrations and the PCr/beta-ATP ratio of the transplants. We correlated the biochemical data to haematoxylin and eosin (H & E) stained tissue slides scored for rejection, infiltration of antibodies and complement depositions, DNA extraction and gel electrophoresis of labeled DNA (DNA laddering), in situ 3'-end labeling of DNA (TUNEL) and the apoptosis specific hairpin probe assays scoring. RESULTS: The rejection score of the xeno grafts differed significantly compared to their syngeneic hamster to hamster controls (2.40 +/- 0.25 vs. 1.20 +/- 0.20; P=0.005) and they had a significantly higher TUNEL score, 228 +/- 15 vs. 2.44 +/- 0.32 (P=0.009), that correlated to changes in PCr concentration (P<0.001) and to the PCr/beta-ATP ratio (P=0.01). The uptake was mainly (90-95%) located to 1-2 microm large extra cellular 'granule'. A picture resembling early necrosis was seen on the H & E stainings and reflected in the Billingham rejection score above. CONCLUSIONS: After 6 h of RP the onset of acute rejection in the concordant hamster xeno hearts displayed features of early, possibly mitochondrial, necrosis, but not apoptosis, which correlated to changes in the PCr concentration and the PCr/beta-ATP ratio. The mechanism for the early rejection observed is unclear and might be caused by other factors in the sera apart from cellular components, antibodies and complement factors. Identification of the underlying mechanisms could enable us to design rational therapies that prevent activation of the recipient's innate immune response.
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- Corbascio, Matthias, et al.
(författare)
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CTLA4Ig combined with anti-LFA-1 prolongs cardiac allograft survival indefinitely.
- 2002
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Ingår i: Transplant Immunology. - 1878-5492. ; 10:1, s. 55-61
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Tidskriftsartikel (refereegranskat)abstract
- CTLA4Ig and anti-LFA-1 are members of a new generation of immunomodulatory drugs which inhibit important signaling pathways in T cell activation. Both substances target molecules which have pivitol functions in the activation of CD4+ and CD8+ T cells and have been theorized to have an interdependent relationship. These drugs have been used independently in various treatment regimens and have shown great promise in prolonging the survival of allografts. In order to test whether these substances have synergistic or potentiating effects when combined, we performed mixed lymphocyte reactions, skin transplantation and vascularised heterotopic heart transplantation in the Balb/c (H-2(d)) to C3H/HeJ (H-2(k)) strain combination. When anti-LFA-1 and CTLA4Ig were combined at low doses, there was a substantial inhibition of lymphocyte proliferation. When each drug was used as a mono-therapy in skin graft recipients, there was no significant effect on median graft survival (anti-LFA-1, 15 days; CTLA4Ig, 16 days) when compared to untreated controls (13 days), whereas a combination of anti-LFA-1 and CTLA4Ig extended graft survival significantly to 32 days. Untreated vascularised heart grafts rejected at a median of 8 days, CTLA4Ig-treated mice rejected at a median time of 79 days and anti-LFA-1-treated mice rejected at 43 days (n = 9). When CTLA4Ig and anti-LFA-1 were combined, all animals had functioning heart grafts at 100 days after transplantation. Histological analysis of combined-therapy hearts showed no signs or only minor changes associated with chronic rejection. In conclusion, these results indicate a synergistic effect of combining anti-LFA-1 with CTLA4Ig in inhibiting lymphocyte proliferation and prolonging the survival of fully MHC-mismatched allografts.
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- Östraat, Ö., et al.
(författare)
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Thalidomide prolonged graft survival in a rat cardiac transplant model but had no inhibitory effect on lymphocyte function in vitro
- 1996
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Ingår i: Transplant Immunology. - 1878-5492. ; 4:2, s. 117-125
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Tidskriftsartikel (refereegranskat)abstract
- The effects of thalidomide on in vitro interleukin 2 (IL-2) production and thymidine uptake by human peripheral blood lymphocytes or rat splenocytes were investigated. Phytohaemagglutinin-stimulated human lymphocytes were incubated in the presence of thalidomide added at culture initiation. No immunosuppressive effect of thalidomide was observed in these experiments. Primary human mixed lymphocyte cultures treated with thalidomide for 6 days were also unaffected. A microsomal rabbit liver homogenate was prepared for metabolizing thalidomide. Stimulated lymphocytes secreted significantly more IL-2 in the presence of microsomal-treated thalidomide than did controls. The effect of thalidomide was then studied either as single therapy or in combination with cyclosporin A (CyA) in a rat allograft cardiac transplantation model. In addition, T cell subsets were analysed by flow cytometry in untransplanted rats treated with thalidomide. Treatment was given as induction therapy from the day of transplantation until day 9. Graft survival in rats treated with thalidomide was significantly prolonged compared to the untreated group. No difference in graft survival was detected between rats treated with thalidomide or CyA only. Graft survival was found to be slightly prolonged in rats given thalidomide and CyA in combination compared to rats treated with CyA alone. In untransplanted rats given thalidomide a decrease of CD4 positive T cells was detected on days 3 and 5. The T helper/cytotoxic-suppressor cell ratio was significantly diminished but, after 1 week of treatment, values for T cell subsets had almost returned to baseline levels. No inhibitory effect was obtained when phytohaemagglutinin-stimulated rat splenocytes were cultured with metabolized thalidomide.In summary, the ability of thalidomide to improve allograft survival in a solid organ transplant model was verified. The occurrence of thalidomide-induced changes in T cell subset ratios was demonstrated. In in vitro studies, however, there was no decrease but an increase in IL-2 production, and no change in thymidine uptake. The mechanism responsible for the immunosuppressive effect of thalidomide remains to be elucidated.
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