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Rutemark, Christian, et al.
(författare)
B cells lacking complement receptors 1 and 2 are equally efficient producers of IgG in vivo as wildtype B cells
Annan publikation (övrigt vetenskapligt/konstnärligt) abstract
The complement system, including the complement receptors 1 and 2 (CR1/2), is crucial for the development of antibody responses against a wide range of antigens. Cr2-/- mice are deficient in both CR1 and CR2 and respond poorly upon immunization with antigen alone and with IgM-containing immune complexes. In mice, CR1/2 are expressed exclusively on B cells and follicular dendritic cells (FDC) but it is not clear which of the two cell-types that need to express the receptors for a normal antibody response. Here, bone marrow chimeras were used to distinguish between B cells and FDC. The animals were immunized with SRBC alone or with IgM anti-SRBC and SRBC. For an antibody response to SRBC alone, CR1/2 expression on FDC was crucial. When CR1/2+ FDC were present, B cells from Cr2-/- mice produced equal amounts of antibodies against SRBC as did B cells from WT. However, the response to IgM-SRBC complexes was more efficient in the presence of CR1/2+ B cells although CR1/2+ FDC still played a dominant role. In conclusion, antibody responses to antigen alone required CR1/2+ FDC, whereas CR1/2 expression on B cells was irrelevant. In contrast, in antibody responses to IgM-IC, presence of CR1/2+ B cells led to a higher and more rapid onset of the antibody response.
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Mohajershojai, Tabassom, et al.
(författare)
PD-1 blockade enhances therapeutic effects of 177Lu-DOTA-M5A in colorectal cancer CEA-transgenic mice
Annan publikation (övrigt vetenskapligt/konstnärligt) abstract
Radioimmunotherapy (RIT) is emerging as an effective treatment for metastatic solid tumors by coupling radionuclides with tumor-targeting molecules, precisely directing radiation to cancer cells while sparing healthy tissue. Carcinoembryonic antigen (CEA) is a promising target for RIT in CEA-expressing cancers, including colorectal cancers (CRCs). Recent studies highlight radiotherapy's role in enhancing the immune response against cancer. Combining RIT with immune checkpoint inhibitors, such as anti-PD-1 antibodies, may further enhance anti-tumor immunity and improve outcomes. This study aimed to investigate, for the first time, the in vivo effects of CEA-targeted RIT using the novel humanized anti-CEA antibody hT84.66-M5A labeled with 177Lu (177Lu-DOTA-M5A), combined with PD-1 blockade. Radioconjugate uptake and therapeutic effects were first assessed in vitro using the CRC spheroid model MC38-CEA1. The therapeutic effects of 177Lu-DOTA-M5A and PD-1 blockade were then evaluated alone or in combination in CEA-transgenic mice bearing CEA-transduced CRC xenografts, with radioconjugate uptake validated in biodistribution studies and visualized via SPECT/CT imaging. Dose-dependent therapeutic effects of 177Lu-DOTA-M5A were demonstrated in the 3D spheroid model. In vivo studies showed that both 177Lu-DOTA-M5A and PD-1 antibody monotherapies effectively reduced tumor growth rates compared to the control group, but the combination therapy had the most significant impact. Combination therapy resulted in a dramatic tumor growth inhibition rate of -6% average daily, compared to +7%, +7.9%, and +13.5% in the PD-1 blockade, 177Lu-DOTA-M5A (2.5 MBq), and control groups, respectively. Median survival increased by 31% in the PD-1 blockade group and by 52% in the 177Lu-DOTA-M5A (2.5 MBq) group compared to the control group, while median survival was not reached in the corresponding combination group. Radioconjugate monotherapies and combination therapies did not introduce any bone marrow toxicity. 177Lu-DOTA-M5A slightly altered the immune cell profile in the tumor microenvironment, increasing cytotoxic and helper T cells. Notably, pro-inflammatory macrophages became dominant over tumor-promoting ones in the tumor microenvironment of combination-treated mice. These findings highlight the promise of 177Lu-DOTA-M5A as a CRC therapeutic agent and its enhanced efficacy when combined with an immune checkpoint inhibitor. Further in vivo studies are needed to fully validate these findings and explore the treatment’s potential for clinical use.
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Björk, Emma, 1977-, et al.
(författare)
Endometriotic tissue-derived exosomes downregulate NKG2D-mediated cytotoxicity and promote apoptosis : mechanisms for survival of endometriotic tissue at ectopic sites
2024
Annan publikation (övrigt vetenskapligt/konstnärligt) abstract
Endometriosis, affecting 10% of women, is defined as implantation, survival, and growth of endometriumlike/endometriotic tissue outside the uterine cavity, causing inflammation, infertility, pain andsusceptibility to ovarian cancer. Despite extensive studies, its etiology and pathogenesis are poorlyunderstood and largely unknown. The prevailing view is that the immune system of endometriosispatients fails to clear ectopically disseminated endometrium from retrograde menstruation. Exosomes aresmall extracellular vesicles that exhibit immunomodulatory properties. We studied the role ofendometriotic tissue-secreted exosomes in the pathophysiology of endometriosis. Two exosome-mediatedmechanisms known to impair the immune response were investigated: 1) downregulation of NKG2Dmediatedcytotoxicity and 2) FasL- and TRAIL-induced apoptosis of activated immune cells. We showedthat secreted endometriotic exosomes isolated from supernatants of short-term explant cultures carry theNKG2D ligands MICA/B and ULBP1-3; and the proapoptotic molecules FasL and TRAIL on theirsurface, i.e. signature molecules of exosome-mediated immune suppression. Acting as decoys, theseexosomes downregulate the NKG2D receptor, impair NKG2D-mediated cytotoxicity and induce apoptosisof activated PBMC and Jurkat cells through the FasL- and TRAIL pathway. The secreted endometrioticexosomes create an immunosuppressive gradient at the ectopic site, forming a “protective shield” aroundthe endometriotic lesions. This gradient guards the endometriotic lesions against clearance by a cytotoxicattack and creates immunologic privilege by induction of apoptosis in activated immune cells. Takentogether, our results provide a plausible, exosome-based mechanistic explanation for the immunedysfunction and the compromised immune surveillance in endometriosis and contribute with novelinsights into the pathogenesis of this enigmatic disease.
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Björk, Emma, et al.
(författare)
Enhanced CD56 expression and increased numbers of CD56+bright cells in the peripheral blood of untreated endometriosis patients
Annan publikation (övrigt vetenskapligt/konstnärligt) abstract
Problem: Endometriosis is characterized by ectopic implantation of endometrial-like tissue and impaired immuneresponses such as the cytotoxic function of NK cells. NK cells can be divided into two subpopulations where theCD56+bright cells produce more cytokines and have low natural cytotoxicity compared to CD56+dim cells. Themajority (>90%) of circulating NK cells are CD56+dim whereas very few (0-10 %) are CD56+bright.Method of Study: Using flow cytometry, NK cell subpopulations were analyzed in peripheral blood from 21individuals with endometriosis and 12 healthy controls. Furthermore, the NKG2D receptor expression on PBMCswas analyzed in untreated and treated endometriosis patients and controls.Results: We found an increased level of CD56+bright cells in 8 of 21 endometriosis patients. After surgery andhormonal treatment, the levels were normalized to that of controls. In a new cohort, the NKG2D receptorexpression on PBMCs was analyzed, with a lower expression in untreated patients compared to controls andpatients treated by surgery and hormones.Conclusions: Our findings of a dominant CD56+bright NK cell subpopulation in peripheral blood, anddownregulated levels of the NKG2D receptor on PBMCs, may explain the impaired cytotoxic immune functioncausing the persistence of ectopic endometrium in untreated endometriosis patients.
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Mullazehi, Mohammed, 1966-, et al.
(författare)
Anti-type II collagen-IC-induced production of IL-1β and TNF-α, stimulate production of matrix met-alloproteinases from monocytes/rheumatoid arthritis synovial fibroblast co-cultures
Annan publikation (övrigt vetenskapligt/konstnärligt) abstract
Objective: To establish an in vitro model that might explain the association between early joint destruction and the appearance of collagen type II (CII) antibodies in early Rheumatoid Arthritis (RA) patients. This RA pannus tissue model utilizes immune complexes (IC) containing CII-antibodies as stimulus and monocytes and synovial fibroblastsas responder cells. Methods: Peripheral blood mononuclear cells (PBMC) and RA synovial fibroblasts (RASF) were stimulated with IC individually as well in co-cultures. Monocytes were depleted to define the responder cells, and TNF-α and IL-1β were neutralized to study the effect on MMP production. TNF-α, IL-1β, MMP-1, MMP-8 and MMP-13 were measured in cell culture super-natants using ELISA.Results: Anti-CII-containing IC induced production of TNF-α, IL-1β and MMP-1 in PBMC cultures, and TNF-α, IL-1β, MMP-1 and MMP-8 in PBMC/fibroblast co-cultures, in a dose-dependent manner. IC-induced MMP-1 responses were stronger and more associated with induced produc-tion of IL-1β as compared to MMP-8 responses. Baseline production of IL-1β and MMP-1 increased significantly in co-cultures as compared to indi-vidual cultures, whereas this was not the effect for TNF-α and MMP-8. Monocyte depletion decreased TNF-α, IL-1β and MMP-1 production, while the effect on MMP-8 production was variable. Cytokine neutralization re-vealed that IL-1β was a stronger inducer of MMP-1 than was TNF-α.Conclusion:Synergistic actions between RASF and PBMC result in enhanced anti-CII IC-induced production of IL-1β and MMP-1. IL-1β and MMP-1 are regu-lated in parallel as anti-CII IC-induced IL-1β supports the production of MMP-1. MMP-8 seems to be regulated by other means. Anti-CII IC-induced TNF-α seems to be inferior to IL-1β concerning MMP-1 induction. The fact that IC stimulated synovial macrophages and fibroblasts to produce MMP, which are the first enzymes to cleave the interstitial collagens may explain the anti-CII-associated joint destruction apparent in early RA.
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