Analysis of graft-versus-host disease (GVHD) and graft rejection using MHC class I-deficient mice

Abstract

GVHD is a major complication in allogeneic bone marrow transplantation (BMT). MHC class I mismatching increases GVHD, but in MHC-matched BMT minor histocompatibility antigens (mH) presented by MHC class I result in significant GVHD. To examine the modification of GVHD in the absence of cell surface MHC class I molecules, beta2-microglobulin-deficient mice (beta2m(-/-)) were used as allogeneic BMT recipients in MHC- and mH-mismatched transplants. Beta2m(-/-) mice accepted MHC class I-expressing BM grafts and developed significant GVHD. MHC (H-2)-mismatched recipients developed acute lethal GVHD. In contrast, animals transplanted across mH barriers developed indolent chronic disease that was eventually fatal. Engrafted splenic T cells in all beta2m(-/-) recipients were predominantly CD3+alphabetaTCR+CD4+ cells (15-20% of all splenocytes). In contrast, CD8+ cells engrafted in very small numbers (1-5%) irrespective of the degree of MHC mismatching. T cells proliferated against recipient strain antigens and recognized recipient strain targets in cytolytic assays. Cytolysis was blocked by anti-MHC class II but not anti-CD8 or anti-MHC class I monoclonal antibodies (MoAbs). Cytolytic CD4+ T cells induced and maintained GVHD in mH-mismatched beta2m(-/-) mice, supporting endogenous mH presentation solely by MHC class II. Conversely, haematopoietic beta2m(-/-) cells were unable to engraft in normal MHC-matched recipients, presumably due to natural killer (NK)-mediated rejection of class I-negative cells. Donor-derived lymphokine-activated killer cells (LAK) were unable to overcome graft rejection (GR) and support engraftment.

The DBY gene codes for an HLA-DQ5–restricted human male-specific minor histocompatibility antigen involved in graft-versus-host disease

“…In MHC class I-deficient mice, CD4 ϩ CTLs induced and maintained GVH disease after allogeneic mHag-mismatched stem cell transplantation. 24 Moreover, transgenic female mice that expressed the T-cell receptor (TCR) from a MHC class II-restricted H-Y-specific T-cell clone rapidly rejected male skin grafts in a CD4-dependent fashion. 25 Recently, it was demonstrated that this T-cell clone recognized an epitope derived from the murine DBY protein.…”

Stable T-cell reactivity after successful tapering of azathioprine in HLA-identical living-related kidney transplant recipients despite minor histocompatibility antigen mismatches

“…Animal studies have shown that mHAgs are involved in the development of allograft arteriosclerosis, GVHD and skin graft rejection [35][36][37][38]. In humans, the influence of mHAgs on transplant outcome has mostly been seen after BMT [12,39].…”

Successful Tapering of Immunosuppression to Low-Dose Monotherapy Steroids After Living-Related Human Leukocyte Antigen-Identical Renal Transplantation

“…These superior results are because HLA-identical LR transplants are less immunogenic than nonidentical renal transplants, because in HLA-identical LR RTx all major (class I and II) HLA molecules are identical and only mismatches in minor histocompatibility antigens (mHAgs) or non-HLA antigens may exist. In animal models, the importance of mHAgs has been shown after cardiac transplantation and allogeneic bone marrow transplantation (1)(2)(3)(4)(5). In humans, mismatches in mHAgs have been shown to induce graft-versus-host disease after HLA-identical bone marrow transplantation, but minor HLA mismatches had no influence on 5-year graft outcome after RTx (6,7).…”