MiHA Reactive CD4 and CD8 T-Cells Effect Resistance to Hematopoietic Engraftment Following Reduced Intensity Conditioning

Abstract

Reduced intensity conditioning (RIC) prior to allogeneic hematopoietic cell transplantation (HCT) has shown promise in lowering the incidence of posttransplant complications including infection and graftversus-host disease. T-cell-mediated graft rejection, however, remains a crucial factor in determining how 'mild' a level of immunosuppression can be administered. Understanding the kinetics of resistance responses as well as the role of CD4 + and CD8 + T cells underlies the development of protocols to circumvent resistance and support hematopoietic engraftment. In these studies, a major histocompatibility complex (MHC)-matched/minor histocompatibility antigen (MiHA) disparate RIC HCT model was developed in which resistance against donor hematopoietic progenitors as well as mature peripheral blood cells could be assessed. Interestingly, resistance was diminished in the absence of either host CD4 + or CD8 + T cells. However, its impairment was more severe in CD4 −/− mice where resistance was not detected. Host CD4 + T cells were required for optimal expansion of specific (H60) T-cell receptor (TCR) expressing host anti-donor MiHA reactive CD8 + T cells following HCT. These observations demonstrate a critical role for host CD4 + T cells in resistance against MiHA disparate HCT. This RIC HCT resistance model will be useful for the analysis of the barrier to engraftment mediated by host T cells and the development of strategies to support engraftment.

Expansion of donor-reactive host T cells in primary graft failure after allogeneic hematopoietic SCT following reduced-intensity conditioning

“…We found graft rejection was associated with an increase in numbers of host T cells in the peripheral blood three weeks after BMT and expansion of cytotoxic CD8 þ T cells in the hematopoietic tissues, BM and spleen. These results correspond with the previous experimental studies that CD8-deficient recipient mice were superior for engraftment 32,33 and that preconditioning with anti-CD8 mAb enhanced allogeneic engraftment. 34 Given that host T cells selectively targeted donor-type cells (Figure 2), these host T cells should recognize donor-type MHC and minor histocompatibility antigens directly presented on donor APCs or indirectly presented on host APCs.…”

A chromosome 16 quantitative trait locus regulates allogeneic bone marrow engraftment in nonmyeloablated mice

“…Reliable engraftment was also achieved when anti-CD4 was combined with anti-CD8 before TBI 300 cGy. These data show that immune resistance in our mice-like other MHCmatched, minor histocompatibility antigen-mismatched mouse models 28 -is mediated primarily by host T cells.…”

Tolerance induction with gene-modified stem cells and immune-preserving conditioning in primed mice: restricting antigen to differentiated antigen-presenting cells permits efficacy

“…14,32,33 A potential difficulty of limiting immune ablation is that recipient T cells can exert considerable immune-resistance to cells expressing endogenous, transgenic or virally engineered neoantigens leading to cellular rejection, and in the case of BMT or HSCT, graft failure. [34][35][36] This could be particularly problematic in an autoimmune disease setting where recipients have expanded populations of memory and effector cells specific for the proteins to be encoded by transferred BM/HSPCs. 37 Targeting therapeutic gene expression to fully differentiated APCs and avoiding expression in stem or progenitor cells is an effective route around the problem of immune-resistance to engraftment of gene-modified BM.…”