Delayed Cytotoxic T Lymphocyte–Associated Protein 4–Immunoglobulin Treatment Reverses Ongoing Alloantibody Responses and Rescues Allografts From Acute Rejection

Abstract

Antibody-mediated rejection has emerged as the leading cause of late graft loss in kidney transplant recipients, and inhibition of donor-specific antibody production should lead to improved transplant outcomes. The fusion protein CTLA4-Ig blocks T-cell activation and consequently inhibits T-dependent B cell antibody production, and the current paradigm is that CTLA4-Ig is effective on naïve T cells and less so on activated or memory T cells. In this study, we used a mouse model of allo-sensitization to investigate the efficacy of continuous CTLA4-Ig treatment, initiated 7 or 14 days post-sensitization, at inhibiting ongoing allo-specific B cell responses. Delayed treatment with CTLA4-Ig collapsed the allo-specific germinal center (GC) B cell response and inhibited alloantibody production. Using adoptively transferred TCR-transgenic T cells and a novel approach to track endogenous graft-specific T cells, we demonstrate that delayed CTLA4-Ig minimally inhibited graft-specific CD4+ and T follicular helper (Tfh) responses. Remarkably, delaying CTLA4-Ig until day 6 post-transplantation in a fully-mismatched heart transplant model inhibited alloantibody production and prevented acute rejection, while transferred hyperimmune sera reversed the effects delayed CTLA4-Ig. Collectively, our studies revealed the unexpected efficacy of CTLA4-Ig at inhibiting ongoing B cell responses even when the graft-specific T cell response has been robustly established.

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.…”

“…Donor B/c.2W-OVA-transgenic mice were backcrossed from B/6-2W-OVA mice for 6 to 9 generations. Heart transplantation, flow cytometry, and H&E staining were performed as previously reported (18). In some experiments, B/6 mice sensitized with B/c-2W-OVA or B/c splenocytes, received, upon B/c-2W-OVA heart transplantation, 500 μg of CTLA4-Ig/mouse (abatacept; Bristol-Myers Squibb) on days -2, 0, and 2 (i.v.…”

Distinct Graft-Specific TCR Avidity Profiles during Acute Rejection and Tolerance

“…Using mouse pMHC multimers to track endogenous graftreactive T cells specific for model donor antigens (Young et al, 2016), we here report that during productive alloimmunity, endogenous CD4 + and CD8 + T cells increased in avidity for alloantigen at the population level. In contrast, following therapeutically induced peripheral tolerance, the avidity profile of T cell populations remained low and comparable to that of naive populations, despite upregulation of CD44 expression by tolerant T cells.…”

Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies

“…Treatment of mice with cytotoxic T lymphocyte-associated protein-4-Ig (CTLA4-Ig) prevented alloantibody production when given in the first 2 weeks after sensitization (69,70). Similarly, the CTLA4-Ig fusion protein belatacept reduced the risk of dnDSA formation in low-risk transplant patients (71).…”