B Cell-Mediated Antigen Presentation Is Required for the Pathogenesis of Acute Cardiac Allograft Rejection

Noorchashm, Hooman; Reed, Amy J.; Rostami, Susan; Mozaffari, Raha; Zekavat, Ghazal; Koeberlein, Brigitte; Caton, Andrew J.; Naji, Ali

doi:10.4049/jimmunol.177.11.7715

Cited by 121 publications

(101 citation statements)

References 37 publications

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“…Recent studies by Naji and colleagues revealed that allograft rejection is impaired in recipients with MHC class II-deficient B cells, which are unable to engage in cognate interactions with CD4 ϩ T cells (30). These observations support the notion that B cells may be critical APCs for stimulating alloreactive CD4…”

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confidence: 75%

Memory Alloreactive B Cells and Alloantibodies Prevent Anti-CD154-Mediated Allograft Acceptance

Burns

et al. 2009

The Journal of Immunology

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The impact of memory B cells and alloantibodies on the ability to induce transplantation tolerance has not been elucidated. We have developed a murine heart transplant model that isolates the contributions of functional memory B cells from memory T cells in allograft rejection. Memory 3-83 B cells with dual specificity for H-2Kk and H-2Kb were generated in 3-83 Igi BCR knockin (BALB/c background) mice by the transplantation of C3H (H-2Kk) hearts in the absence of immunosuppression. To test the effect of functional memory 3-83 B cells, C3H-primed 3-83 Igi recipients were challenged with C57BL/6 hearts (H-2Kb) at 60–90 days post-C3H heart transplant and treated with anti-CD154 mAbs. Despite immunosuppression, the C57BL/6 hearts were acutely rejected within 10–13 days and graft rejection was associated with increased frequencies of C57BL/6-specific IFN-γ-producing T cells. Histology revealed significant numbers of infiltrating T cells, consistent with acute T cell-mediated rejection. The resistance to tolerance induction was dependent on the synergistic effects of memory 3-83 B cells and alloantibodies, whereas memory T cells are not necessary. We conclude that the combined effects of functional memory B cells and alloantibodies prevent anti-CD154-mediated graft acceptance by facilitating the CD40-CD154-independent activation of alloreactive T cells. This study provides insight into the potential ability of memory B cells and alloantibodies to prevent anti-CD154-mediated graft acceptance.

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confidence: 75%

Memory Alloreactive B Cells and Alloantibodies Prevent Anti-CD154-Mediated Allograft Acceptance

Burns

et al. 2009

The Journal of Immunology

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“…These are preferentially taken up by APCs via their Fc or complement receptors, eventually leading to their maturation and potent stimulation of alloreactive T cells (38,39). A study by Noorchashm et al (40) confirmed that B cells themselves can effectively act as APCs and are an important contributor to T cell activation and allograft rejection in a murine cardiac allograft model. This work was extended by Burns et al (41), who showed that preformed alloantibodies caused resistance to tolerance induction protocols.…”

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confidence: 81%

Targeting MHC Class I Monomers to Dendritic Cells Inhibits the Indirect Pathway of Allorecognition and the Production of IgG Alloantibodies Leading to Long-Term Allograft Survival

Tanriver

Ratnasothy

Bucy

et al. 2010

The Journal of Immunology

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T cell depletion strategies are an efficient therapy for the treatment of acute rejections and are an essential part of tolerance induction protocols in various animal models; however, they are usually nonselective and cause wholesale T cell depletion leaving the individual in a severely immunocompromised state. So far it has been difficult to selectively delete alloreactive T cells because the majority of protocols either delete all T cells, subsets of T cells, or subpopulations of T cells expressing certain activation markers, ignoring the Ag specificity of the TCR. We have developed a model in which we were able to selectively deplete alloreactive T cells with an indirect specificity by targeting intact MHC molecules to quiescent dendritic cells using 33D1 as the targeting Ab. This strategy enabled us to inhibit the indirect alloresponse against MHC-mismatched skin grafts and hence the generation of IgG alloantibodies, which depends on indirectly activated T cells. In combination with the temporary abrogation of the direct alloresponse, we were able to induce indefinite skin graft survival. Importantly, the targeting strategy had no detrimental effect on CD4+CD25+FoxP3+ T cells, which could potentially be used as an adjunctive cellular therapy. Transplantation tolerance depends on the right balance between depletion and regulation. For the former this approach may be a useful tool in the development of future tolerance induction protocols in non-sensitized patients.

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“…A lthough B-cells have been primarily considered antibody-producing cells, recent studies demonstrate that they participate in the priming of autoimmune responses (1,2). Many investigations have examined the role of B-cells as antigen-presenting cells (APCs) in the generation of autoreactive T-cell responses (3,4).…”

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confidence: 99%

Targeting CD22 Reprograms B-Cells and Reverses Autoimmune Diabetes

et al. 2008

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OBJECTIVES-To investigate a B-cell-depleting strategy to reverse diabetes in naïve NOD mice. RESEARCH DESIGN AND METHODS-We targeted the CD22 receptor on B-cells of naïve NOD mice to deplete and reprogram B-cells to effectively reverse autoimmune diabetes.RESULTS-Anti-CD22/cal monoclonal antibody (mAb) therapy resulted in early and prolonged B-cell depletion and delayed disease in pre-diabetic mice. Importantly, when new-onset hyperglycemic mice were treated with the anti-CD22/cal mAb, 100% of B-celldepleted mice became normoglycemic by 2 days, and 70% of them maintained a state of long-term normoglycemia. Early therapy after onset of hyperglycemia and complete B-cell depletion are essential for optimal efficacy. Treated mice showed an increase in percentage of regulatory T-cells in islets and pancreatic lymph nodes and a diminished immune response to islet peptides in vitro. Transcriptome analysis of reemerging B-cells showed significant changes of a set of proinflammatory genes. Functionally, reemerging B-cells failed to present autoantigen and prevented diabetes when cotransferred with autoreactive CD4 ϩ T-cells into NOD.SCID hosts. Most individuals affected by type 1 diabetes exhibit multiple features associated with impaired B-cell function, including autoantibodies against a variety of islet cell antigens (6,7). Data from different groups using NOD mice, the best animal model for the study of type 1 diabetes, have confirmed the importance of B-cells in the onset of diabetes (2-4,8,9). NOD mice that are deficient in B-cells have been shown to be protected from autoimmune diabetes (3,10,11) and are deficient in the development of a T-cell response to major autoantigens (such as 65-kDa glutamate decarboxylase) (3,10,11). In humans, the production of autoantibodies to islet antigens is well documented as an early indicator of disease onset (12). These observations render B-cell targeting a particularly attractive and novel strategy for the treatment of type 1 diabetes (13-15). Unfortunately, this strategy has not been fully described in naïve NOD mice. Only recently did a publication show the positive effects of an anti-CD20 -based B-cell-depleting strategy in transgenic NOD mice expressing the humanized CD20 receptor on B-cells (8). Interestingly, use of B-cell depletion as a therapy for human autoimmune disease (16 -20), including in patients with new-onset type 1 diabetes, is ongoing (21,22). CONCLUSIONS-TargetingWe made use of a newly developed reagent (anti-CD22 calicheamicin-conjugated monoclonal antibody [anti-CD22/cal mAb]) that efficiently depletes mature B-cells in mice (13) to establish a therapeutic approach for type 1 diabetes. Our main hypothesis was that depleting B-cells by targeting CD22 should prevent diabetes onset and restore normoglycemia in newly hyperglycemic NOD mice. Furthermore, we hypothesize that our approach will generate a pool of reemerging B-cells that may function to regulate the autoimmune response in vivo, establishing a state of long-term tolerance toward autoantigens. RESEA...

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B Cell-Mediated Antigen Presentation Is Required for the Pathogenesis of Acute Cardiac Allograft Rejection

Cited by 121 publications

References 37 publications

Memory Alloreactive B Cells and Alloantibodies Prevent Anti-CD154-Mediated Allograft Acceptance

Memory Alloreactive B Cells and Alloantibodies Prevent Anti-CD154-Mediated Allograft Acceptance

Targeting MHC Class I Monomers to Dendritic Cells Inhibits the Indirect Pathway of Allorecognition and the Production of IgG Alloantibodies Leading to Long-Term Allograft Survival

Targeting CD22 Reprograms B-Cells and Reverses Autoimmune Diabetes

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