Costimulation Blockade Alters Germinal Center Responses and Prevents Antibody-Mediated Rejection

Abstract

De novo donor-specific antibody (DSA) after organ transplantation promotes antibody-mediated rejection (AMR) and causes late graft loss. Previously, we demonstrated that depletion using anti-CD3 immunotoxin (IT) combined with tacrolimus and alefacept (AMR regimen) reliably induced early DSA production with AMR in a nonhuman primate kidney transplant model. Five animals were assigned as positive AMR controls, four received additional belatacept, and four received additional anti-CD40 mAb (2C10R4R4). Notably, production of early de novo DSA was completely attenuated with additional belatacept or 2C10R4R4 treatment. In accordance with this, while positive controls experienced a decrease in peripheral IgM+ B cells, bela- and 2C10R4-added groups maintained a predominant population of IgM+ B cells, potentially indicating decreased isotype switching. Central memory T cells (CD4+CD28+CD95+) as well as PD1hiCD4+ T cells were decreased in both bela-added and 2C10R4-added groups. In analyzing germinal center (GC) reactions in situ, lymph nodes further revealed a reduction of B cell clonal expansion, GC-Tfh cells, and IL-21 production inside germinal centers with additional belatacept or 2C10R4 treatment. Here we provide evidence that belatacept and 2C10R4 selectively suppresses the humoral response via regulating follicular helper T cells and prevents AMR in this non-human primate model.

CTLA4-Ig in combination with FTY720 promotes allograft survival in sensitized recipients

“…We and others have reported that CTLA4-Ig inhibits early T cell-dependent alloantibody responses as well as recall responses (15)(16)(17)(18). In this study, we extend those observations by characterizing the impact of extended CTLA4-Ig treatment on graft-reactive memory T cell responses.…”

T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway

“…37,38 An example of this statement is the efficacy of CD40L/CD40 targeting in preclinical and clinical settings of transplantation and autoimmune disease. 39,40 The data presented herein demonstrate that modulation of BTLA/HVEM pathway does not affect Tfh cell expansion, GC reactions or the de novo formation of host antidonor allogeneic antibodies. BTLA, like other members of the immunoglobulin superfamily, such as CTLA4 and PD1, functions as a co-inhibitory receptor of the immunoglobulin superfamily.…”

Strategies to Inhibit Alloantibody Production in Alloprimed Murine Recipients of Hematopoietic Stem Cell Grafts

“…Our studies build upon previous work by others demonstrating that costimulatory signal deliver by helper T cells, predominantly transmitted via the indirect pathway of allorecognition, are required for induction of high titer, isotype switched, IgG, alloantibody reactive to donor antigens (7,8,10,(30)(31)(32)(33)(34)(35)(36). Using an allosensitization model in which the prior administration of a single fully MHC disparate splenocyte dose provides sufficient high-titer alloantibody to reject allogeneic BM grafts even 1 year postpriming, we newly demonstrate that only a combination of a highly depletionary anti-CD20 mAb plus LTbR-Ig that reduces GC formation sufficiently eliminates alloantibody to permit donor BM rescue of lethally irradiated, T-and NK-depleted recipients ( Figure 5D).…”