Combined Coinhibitory and Costimulatory Modulation with Anti-BTLA and CTLA4Ig Facilitates Tolerance in Murine Islet Allografts

Abstract

Complex interactions between positive and negative cosignaling receptors ultimately determine the fate of the immune response. The recently identified coinhibitory receptor, B and T lymphocyte attenuator (BTLA), contributes to regulation of autoimmune and potentially alloimmune responses. We investigated the role of BTLA in a fully major histocompatibility complex-mismatched mouse islet transplant model. We report that anti-BTLA mAb (6F7) alone does not accelerate graft rejection. Rather, while CTLA4Ig alone improved allograft survival, the addition of anti-BTLA mAb to CTLA4Ig led to indefinite (>100 days) allograft survival. Immediately after treatment with anti-BTLA mAb and CTLA4Ig, islet allografts showed intact islets and insulin production despite a host cellular response, with local accumulation of Foxp3+ cells. We clearly demonstrate that combined therapy with anti-BTLA mAb and CTLA4Ig mice induced donor-specific tolerance, since mice accepted a second donor-specific islet graft without further treatment and rejected third party grafts. CTLA4Ig and anti-BTLA mAb limited the initial in vivo proliferation of CFSE-labeled allogeneic lymphocytes, and anti-BTLA mAb enhanced the proportion of PD-1 expressing T cells while depleting pathogenic BTLA+ lymphocytes. We conclude that targeting the BTLA pathway in conjunction with CTLA4Ig costimulatory blockade may be a useful strategy for promoting immunological tolerance in murine islet allografts.

B and T Lymphocyte Attenuator Restricts the Protective Immune Response against Experimental Malaria

“…Triggering BTLA or deleting BTLA highly positive T cells also might have therapeutic significance. In a model of cerebral malaria, we have shown that an agonistic Ab can prevent experimental cerebral malaria (14) and others have shown that anti-BTLA can induce delayed onset of diabetes (15), decreased T cell-induced colitis (6), and prolonged allograft survival (15,16).…”

An Agonistic Anti-BTLA mAb (3C10) Induced Generation of IL-10-Dependent Regulatory CD4+ T Cells and Prolongation of Murine Cardiac Allograft

“…Active suppression by regulatory cells is involved in the induction and maintenance of self-tolerance (27,28), unresponsiveness (29), and hyporesponsiveness (30Y35) to allografts. Truong et al (36) have reported that treatment with anti-BTLA mAb plus CTLA-4Ig resulted in the induction of Foxp3 + regulatory T cells within long-term engrafted islets. In the adoptive transfer studies (Fig.…”

Monoclonal antibodies to B and T lymphocyte attenuator (BTLA) have no effect on in vitro B cell proliferation and act to inhibit in vitro T cell proliferation when presented in a cis, but not trans, format relative to the activating stimulus

“…There are few studies that describe the effects of anti-specific anti-BTLA reagents in vivo (as opposed to soluble HVEM-Fc which can bind to other molecules). The study by Truong et al is a novel and interesting study that describes a synergistic improvement in allograft maintenance when the anti-BTLA mAb clone 6F7 is combined with CTLA4-Fc [34]. Specifically, at day 100 post-transplant approximately 40% of the mice treated with CTLA4-Fc alone have survived and approximately 70% of the mice treated with CTLA4-Fc and the mAb 6F7 have survived.…”