Belatacept has emerged with a paradoxical clinical picture including higher rejection rates and a potential signature of impaired viral immunity, particularly in viral-naÏve patients. We performed this study to characterize CMV- and allo-specific reactivity and differentiate the influence of tacrolimus from that of belatacept. Human PBMCs, isolated from CMV seropositive (n=10) and seronegative (n=8) volunteers, were stimulated with allogeneic PBMCs and CMV peptides followed by detection of proliferation and intracellular cytokines using multiparameter flow cytometry. Both CD4+ and CD8+ cells from CMV experienced, but not virally naÏve subjects, responded to CMV peptides characterized as CD28- effector memory cells expressing both IFN-Γ/TNF-Α (CD4+ 0.6%±0.2, CD8+ 0.91%±0.3), many also expressed IL-2 (CD4+ 63.8%±7.7, CD8+ 29.8%±5.4). T cells responded similarly to alloantigen with a high percentage of the repertoire, but proportionately fewer dual producers (CD4+ 1.6%±0.5, CD8+ 6.7%±2.9) and a many fewer IL-2+ cells within IFN-Γ/TNF-Α producers (CD4+: 20.7%±4.4, CD8+: 7.5%±1.1) and many more cells expressing single cytokines (CD4+: TNF-Α+ 2.1%±0.5, IFN-Γ+ 0.4±0.1, CD8+: TNF-Α+ 1.5%±0.7, IFN-Γ+ 1.4%±0.5). Tacrolimus completely inhibited CMV- and allo-specific T cell proliferation and cytokine production. In contrast, belatacept failed to impair triple-cytokine producers targeting CMV or alloantigen. The belatacept displayed bulk effect in the marked reduction in absolute response by paring down cells with limited responsiveness (the majority of allo-response) with comparative little effect of triple producers. Our data indicate that belatacept has a diminishing effect on cells of progressively more developed effector responses, regardless of the target antigen. Since a developed viral-specific response consists exclusively of multi-producer effectors, belatacept has little effect on viral-specific immunity in viral-experienced subjects. Conversely, belatacept has a substantial inhibitory effect on allo-responses consisting with less developed effectors; but in situations where allo-responses incorporate multi-cytokine effectors, belatacept is ineffective against these core responders. Thus, belatacept impairs the bulk of an allo-response leaving pre-established viral or allo-memory unperturbed. These response patterns are consistent with the emerging clinical effects of belatacept, and argue against a differential effect of belatacept on viral versus alloantigens.

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