Potent interaction between CMV reactivation and GVHD: Immunologic evidence for the blunting of CMV-driven immune reconstitution in the setting of GVHD in transplant patients

Abstract

Abstract Allogeneic hematopoietic cell transplantation (HCT) may be curative for patients with marrow and immune disorders, but acute graft-vs-host-disease (aGVHD) and infections cause significant morbidity and non-relapse mortality. We conducted a multicenter, double blind, placebo-controlled phase II trial of costimulation blockade with abatacept (Aba) combined with standard GVHD prophylaxis with a calcineurin inhibitor and methotrexate (CNI + MTX) following HLA matched unrelated donor transplant (n=140). In order to assess whether Aba produces clinically relevant compromise of immune reconstitution, and whether this reconstitution is influenced during CMV reactivation, we longitudinally evaluated post-transplant whole blood samples with multiparameter flow cytometry using markers for CD3, CD4, CD8, CD197 and CD45RA to measure reconstitution of CD4 and CD8 T cell populations and their respective memory subsets over time. We show here that post-transplant CMV reactivation induces a marked expansion of CD8 effector memory (EM) cells, which is similar in Aba vs placebo pts. We found that development of moderate (gr 2–4) or severe (gr 3–4) GVHD does not cause more CMV reactivation in patients, but patients with moderate GVHD show a blunted expansion of CD8 EM cells compared to those without GVHD. Remarkably, CD8 EM expansion was essentially absent among CMV reactivating patients with severe aGVHD. Our results suggest that adding abatacept to CNI/MTX does not materially affect reconstitution of T cell immunity in the presence or absence of CMV reactivation, but aGVHD remains a major driver of compromised immune recovery after HCT.