Nonalloreactive T Cells Prevent Donor Lymphocyte Infusion–Induced Graft-versus-Host Disease by Controlling Microbial Stimuli

Abstract

In mice, graft-versus-host reactions (GVHR), associated with powerful graft-versus-tumor effects, can be achieved without graft-versus-host disease (GVHD) by delayed administration of donor lymphocyte infusions (DLI) to established mixed chimeras (MCs). However, GVHD sometimes occurrs after DLI in established mixed chimeric patients. In contrast to mice, in which T cell recovery from the thymus occurs prior to DLI administration, human T cell reconstitution following T cell-depleted hematopoietic cell transplantation is slow, resulting in lymphopenia at the time of DLI. We demonstrate here that T cell lymphopenia is an independent risk factor for GVHD following DLI in the absence of known inflammatory stimuli. DLI-induced GVHD was prevented in lymphopenic recipients by prior administration of a small number of non-alloreactive polyclonal T cells, insufficient to prevent lymphopenia-associated expansion of subsequently administered T cells, through a Treg-independent mechanism, but not by T cells with irrelevant specificity. Moreover, administration of antibiotics reduced the severity of GVHD in lymphopenic hosts. Accumulation of DLI-derived effector T cells and host hematopoietic cell elimination were markedly diminished by Treg-depleted, non-alloreactive T cells. Finally, thymectomized mixed chimeras showed increased GVHD following delayed DLI. Collectively, our data demonstrate that in the absence of known conditioning-induced inflammatory stimuli, T cell lymphopenia is a risk factor for GVHD in MCs receiving delayed DLI and suggest that the predisposition to GVHD can at least in part be explained by the presence of occult inflammatory stimuli due to the absence of T cells to control microbial infections.

Innate allorecognition

“…In addition, allografts parked in T‐cell‐deficient hosts until tissue injury and microbial contamination that occurred at the time of transplantation have resolved, are uniformly rejected when the host is replenished with T cells . These observations imply that innate stimuli may not be absolutely required for rejection, that unaccounted for microbe‐derived innate stimuli are present in lymphopenic mice , or that additional innate stimuli, other than danger and microbial molecules, may exist in the setting of organ transplantation. Below, we provide evidence in support of the latter hypothesis.…”

Recommendations on Selection and Processing of RBC Components for Pediatric Patients From the Pediatric Critical Care Transfusion and Anemia Expertise Initiative

“…The central aspect of TA-GVHD is the presence of viable donor lymphocytes that react to recipient antigens (11). Host (immune-incompetence), donor T-lymphocyte, and environmental factors (e.g., inflammation) have been implicated in the development of this most often fatal complication of transfusion (12). While TA-GVHD is most commonly diagnosed in immune-incompetent recipients, it has been seen in rare patients with a presumed normal immune system (7).…”

“…HLA mismatch alone is neither sufficient nor required for TA-GVHD to develop (7). Leukoreduction of blood components has been associated with a reduced rate of TA-GVHD on the population level (12), but this alone does not completely eliminate the risk of TA-GVHD (7, 13). Irradiation of cellular blood products (i.e.…”

Human Immune System Mice With Autologous Tumor for Modeling Cancer Immunotherapies

“…We have tested the potential of lymphopenia to enhance antitumor effects of RLI in leukemic HIS mice ( Figure 1 ) ( 38 ). Lymphopenia is common in patients with leukemia who receive allo-HCT ( 49 , 50 ), which is a factor that triggers GVHD ( 51 , 52 ) but also promotes antitumor responses ( 53 , 54 ). In this study, mixed chimeric (MC) HIS mice were established by transplantation of human Thy along with a mixture of ‘recipient’ (genetically identical to the Thy graft) and allogeneic ‘donor’ CD34 + HSCs, and lymphopenia was made by treatment with anti-huCD3-immunotoxin.…”