The Impact of CD154 Pathway Antagonism in Transplantation and Protective Immunity Against Infection Restricted; Files & ToC
Alexander, Katie (Spring 2026)
Abstract
Solid organ transplantation is a key curative treatment for end-stage organ disease. However, current mainstay immunosuppression to prevent rejection, calcineurin inhibitors, are associated with significant multiple organ toxicities and increased risk of malignancy and infection. Costimulation blockade therapy is a promising alternative, however, currently used belatacept (CTLA4-Ig) is associated with increased rates of acute rejection and infectious complications, particularly from Epstein-Barr virus. Anti-CD154 is another promising costimulation blockade that impacts CD154:CD40 signaling necessary for dendritic cell licensing and B cell activation and initiation of the germinal center response. However, the impact of anti-CD154 on the response to infection, in particular to Epstein-Barr virus, is not fully understood.
To address this, we used a murine homolog of Epstein-Barr virus (MHV68) to investigate the impact of anti-CD154 and CD154:CD11b-specific blockade on the response to infection. Murine skin graft models of transplantation were used to compare the response to infection versus transplantation. Mechanistic investigation of CD11b-expressing cells across mouse, non-human primate, and human tissues was conducted. NHP PBMCs were stimulated with donor PBMCs for in vitro mixed lymphocyte reactions to assess the alloresponse, and healthy human PBMCs were stimulated with anti-CD3/28 antibodies.
Overall, this dissertation establishes that CD154 pathway blockade inhibits the alloreactive immune response but, surprisingly, improves the antiviral response to MHV68. This contradictory finding is underscored by baseline differences in CD8+ T cell differentiation in response to a transplant versus infection that is further altered by differential induction of mTOR signaling. These studies also revealed that CD8+ T cells differentially express the myeloid lineage marker CD11b, primarily early in activation, and is isolated to the graft in transplantation, providing a specific target on graft-infiltrating CD8+ T cells. Not only is anti-CD154 a promising costimulation blockade that inhibits alloimmunity but maintains protective immunity against infection, but CD154:CD11b blockade may be an effective adjunctive therapy that can have an unexpected direct effect on CD11b-expressing CD8+ T cells. These findings establish a target that can promote balance in preventing alloimmunity while maintaining protective immunity and advance an effort to prolong transplant survival and improve their quality of life.
Table of Contents
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File download under embargo until 27 May 2028 | 2026-01-27 12:05:12 -0500 | File download under embargo until 27 May 2028 |
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