Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 11, Issue 1, Pages 22-33Publisher
WILEY
DOI: 10.1111/j.1600-6143.2010.03317.x
Keywords
Allotransplantation; co-stimulation blockade; memory CD8 T cells
Categories
Funding
- NIH
- Georgia Research Alliance
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR000454] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [UL1RR025008] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [U01AI079223, P01AI044644, U01AI077821] Funding Source: NIH RePORTER
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Costimulation blockade (CoB), specifically CD28/B7 inhibition with belatacept, is an emerging clinical replacement for calcineurin inhibitor-based immunosuppression in allotransplantation. However, there is accumulating evidence that belatacept incompletely controls alloreactive T cells that lose CD28 expression during terminal differentiation. We have recently shown that the CD2-specific fusion protein alefacept controls costimulation blockade-resistant allograft rejection in nonhuman primates. Here, we have investigated the relationship between human alloreactive T cells, costimulation blockade sensitivity and CD2 expression to determine whether these findings warrant potential clinical translation. Using polychromatic flow cytometry, we found that CD8+ effector memory T cells are distinctly high CD2 and low CD28 expressors. Alloresponsive CD8+CD2hiCD28- T cells contained the highest proportion of cells with polyfunctional cytokine (IFN gamma, TNF and IL-2) and cytotoxic effector molecule (CD107a and granzyme B) expression capability. Treatment with belatacept in vitro incompletely attenuated allospecific proliferation, but alefacept inhibited belatacept-resistant proliferation. These results suggest that highly alloreactive effector T cells exert their late stage functions without reliance on ongoing CD28/B7 costimulation. Their high CD2 expression increases their susceptibility to alefacept. These studies combined with in vivo nonhuman primate data provide a rationale for translation of an immunosuppression regimen pairing alefacept and belatacept to human renal transplantation.
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