The Functional and Histological Basis for Graft‐versus‐Host‐Induced Immunosuppression

Abstract

The GvH reaction resulting from the injection of parental strain cells into adult F1 hybrids suppresses both cell-mediated and humoral immune responses and is dependent on the donor-host combination and the number of parental cells used to induce the GvH reaction. The early suppression is due, at least in part, to the increased number of macrophages and the activation of suppressor macrophages which act directly on the T-helper cell and perhaps the B-cell as well. The macrophage suppression is associated with an increase in PGE production. The long-term T-cell immunodeficiency is mediated by GvH-induced thymic dysplasia resulting in a block or an arrest in T-cell differentiation and deficient IL-2 production. The B-cell immunodeficiency is associated with both a decrease in B-cell production from lymphoid progenitors and a decrease in CFU-s production. The GvH reaction induces 2 types of thymic lesion, a stress-related effect causing atrophy of the thymic cortex and a cytolytic process causing severe-to-moderate lesions in the thymic medulla as a consequence of injury to medullary epithelial cells and a loss of Hassall's corpuscles (thymic dysplasia). By employing the NK-cell-deficient beige mutation, it was shown that the severe-to-moderate thymic medullary lesions occurred in F1 mice only in those transplant situations in which the donor inoculum was of the +/bg genotype, regardless of the genotype of the recipient. It is proposed that activation of parental T cells may contribute to the early immunosuppressive events; however, the relatively permanent immunosuppression appears to be associated with NK-like effector cells which are capable of causing injury to lymphoid and epithelial tissue, especially epithelium of the thymic medulla. These studies raise the possibility that the GvH reaction may contribute to some T- and B-cell immunodeficiencies observed in the SCID and AIDS syndromes, as well as in patients following bone marrow transplantation.

Graft-versus-host-disease-associated lymphoid hypoplasia and B cell dysfunction is dependent upon donor T cell-mediated Fas-ligand function, but not perforin function

“…Notably, it has been shown recently that immature CD4 ϩ CD8 ϩ thymocytes are specifically sensitive to anti-Fas antibody-induced apoptosis (29). Based on our findings concerning lymphoid atrophy in GVHD, we propose that FasL-dependent T cellmediated cytotoxic activity could also induce substantial damage to stromal cells in the recipient bone marrow or to epithelial cells in the recipient thymus contributing to further impairment of normal lymphopoiesis in both compartments (30).…”

Allogeneic T cells impair engraftment and hematopoiesis after stem cell transplantation

“…The body of data demonstrating the deleterious effects of GVHR on BM and lymphoid function (13)(14)(15)(16)(17)(18)(19)(20)(26)(27)(28) is often overlooked or underestimated. We previously reported that even low amounts of T cells cause subclinical, yet lympho-depleting, GVHR (25).…”

Purified hematopoietic stem cell allografts reconstitute immunity superior to bone marrow

“…The desired outcome is the reestablishment of an effective immune system that accurately delineates self from non-self. However, this goal is often confounded by the negative effects of graft-versus-host disease (GVHD), a syndrome caused by donor lymphoid cells that recognize alloantigens and destroy host tissues including lymphoid stroma (4,5). Pharmacotherapy is used to prevent and control GVHD but is ineffective in some patients.…”