Combined Costimulatory and Leukocyte Functional Antigen-1 Blockade Prevents Transplant Rejection Mediated by Heterologous Immune Memory Alloresponses

Abstract

Background Recent evidence suggests that alloreactive memory T cells are generated by the process of heterologous immunity, whereby memory T cells arising in response to pathogen infection cross-react with donor antigens. Due to their diminished requirements for costimulation during recall, these pathogen-elicited allo-crossreactive memory T cells are of particular clinical importance, especially given the emergence of costimulatory blockade as a transplant immunosuppression strategy. Methods We utilized an established model of heterologous immunity involving sequential infection of a naïve C57BL/6 recipient with lymphocytic choriomeningitis virus and vaccinia virus, followed by combined skin and bone marrow transplant from a BALB/c donor. Results We demonstrate that coupling the integrin antagonist anti-LFA-1 with costimulatory blockade could surmount the barrier posed by heterologous immunity in a fully allogeneic murine transplant system. The combined costimulatory and integrin blockade regimen suppressed proliferation of alloreactive memory T cells and attenuated their cytokine effector responses. This combined blockade regimen also promoted the retention of FoxP3+ Tregs in draining lymph nodes. Finally, we show that in an in vitro mixed lymphocyte reaction system using human T cells, the combination of belatacept and anti-LFA-1 was able to suppress cytokine production by alloreactive memory T cells that was resistant to belatacept alone. Conclusions As an antagonist against human LFA-1 exists and has been used clinically to treat psoriasis, these findings have significant translational potential for future clinical transplant trials.

Belatacept-Resistant Rejection Is Associated With CD28+ Memory CD8 T Cells

“…T cell memory phenotype is subject to change based on chronicity of antigen exposure, acuity of infection, or heterologous challenge (19). Consistent with our work, previous studies have identified a highly proliferative and potently cytolytic CD28 + CD8 + T EMRA cell subset in patients vaccinated for yellow fever (50). Additional investigation into the factors contributing to rejection associated with a higher level of CD28 + T EMRA is required.…”

Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model

“…With the redundant presence of adhesion molecules present on immune cells and their target proteins, it is very likely that migration is not dependent solely on LFA-1. Indeed, VLA-4 may play a more significant role for alloreactive CD4 T cell intragraft migration (13, 45). Additionally, prior studies examining adhesion blockade in transplantation may not necessarily distinguish its effects on the immunologic synapse versus memory T cell effector function.…”

Viral-induced CD28 loss evokes costimulation independent alloimmunity

“…While prior studies have established that acute viral infections can induce repertoire changes that lead to CoBRR, the impact of persistent infections, such as BK virus, or latent viruses such as CMV and EBV have been poorly characterized. 6,12-14 In addition, specific attention toward fluctuations in CD28 expression has been lacking, largely because these changes are less overt in mice than in humans. To model these aspects of the human condition, we established a murine model that employs a sequential polyviral infection of the most common relevant human virus homologs: Polyomavirus (BK virus homolog), mCMV (CMV homolog), and HV68 (EBV homolog).…”