The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice

The role of cell-mediated cytotoxicity in the complex pathophysiology of graft-versus-host disease (GVHD) has remained poorly defined for several decades. We transplanted T cells from Fas-ligand (FasL)- defective and perforin-deficient mutant donor mice into lethally irradiated MHC-matched allogeneic recipient mice to characterize the role of cell-mediated cytotoxicity in GVHD. Although recipients of allogeneic FasL-defective donor T cells underwent severe GVHD- associated cachexia, they exhibited only minimal signs of hepatic and cutaneous GVHD pathology. Recipients of perforin-deficient allogeneic donor T cells developed signs of acute GVHD, but the time of onset was significantly delayed. These findings demonstrate that Fas-mediated anti-recipient cytotoxicity may be critical for the development of hepatic and cutaneous GVHD, but is not required for GVHD-associated cachexia. In addition, perforin-mediated anti-recipient cytotoxicity appears to play an important role in the kinetics of GVHD pathophysiology, but is not required for GVHD-associated tissue damage.

[1]  S. Ikehara,et al.  Prevention of lpr-graft-versus-host disease and transfer of autoimmune diseases in normal C57BL/6 mice by transplantation of bone marrow cells plus bones (stromal cells) from MRL/lpr mice. , 1996, Journal of immunology.

[2]  C. Ricordi,et al.  Abrogation of Graft‐versus‐Host Disease Following Allotransplantation of Cytotoxically Deficient Bone Marrow across Major Histocompatibility Barriers , 1995, Annals of the New York Academy of Sciences.

[3]  T. Yokota,et al.  Expression of the Fas ligand in cells of T cell lineage. , 1995, Journal of immunology.

[4]  K. Sayama,et al.  Expression of Fas antigen on keratinocytes in vivo and induction of apoptosis in cultured keratinocytes. , 1994, The Journal of investigative dermatology.

[5]  J. Tschopp,et al.  Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways , 1994, Nature.

[6]  H Hengartner,et al.  Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. , 1994, Science.

[7]  Hans Hengartner,et al.  Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice , 1994, Nature.

[8]  H. Ikeda,et al.  Apoptosis of murine large intestine in acute graft-versus-host disease after allogeneic bone marrow transplantation across minor histocompatibility barriers. , 1994, Transplantation.

[9]  M. Cooley,et al.  Cytotoxic T lymphocyte precursor frequency does not correlate with either the incidence or severity of graft-versus-host disease after matched unrelated donor bone marrow transplantation. , 1994, Transplantation.

[10]  P. Erb,et al.  Fas antigen is the major target molecule for CD4+ T cell-mediated cytotoxicity. , 1994, Journal of immunology.

[11]  D. Speiser,et al.  THE FREQUENCY OF PRETRANSPLANT DONOR CYTOTOXIC T CELL PRECURSORS WITH ANTI‐HOST SPECIFICITY PREDICTS SURVIVAL OF PATIENTS TRANSPLANTED WITH BONE MARROW FROM DONORS OTHER THAN HLA‐IDENTICAL SIBLINGS , 1993, Transplantation.

[12]  S. Nagata,et al.  Lethal effect of the anti-Fas antibody in mice , 1993, Nature.

[13]  J. Sprent,et al.  Characterization of target injury of murine acute graft-versus-host disease directed to multiple minor histocompatibility antigens elicited by either CD4+ or CD8+ effector cells. , 1991, The American journal of pathology.

[14]  R. Korngold,et al.  Immunodominance in the graft-vs-host disease T cell response to minor histocompatibility antigens. , 1990, Journal of immunology.

[15]  J. Marshall,et al.  Differences defined by bone marrow transplantation suggest that lpr and gld are mutations of genes encoding an interacting pair of molecules , 1990, The Journal of experimental medicine.

[16]  W. Lehmacher,et al.  Increased serum levels of tumor necrosis factor alpha precede major complications of bone marrow transplantation. , 1990, Blood.

[17]  G. Klimpel,et al.  Immunosuppression and lymphoid hypoplasia associated with chronic graft versus host disease is dependent upon IFN-gamma production. , 1990, Journal of immunology.

[18]  P. Lipsky,et al.  Lethal graft-vs-host disease induced by a class II MHC antigen only disparity is not mediated by cytotoxic T cells. , 1988, Journal of immunology.

[19]  K. Tracey,et al.  Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation , 1988, The Journal of experimental medicine.

[20]  P. Vassalli,et al.  Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease , 1987, The Journal of experimental medicine.

[21]  P. Lipsky,et al.  Lethal graft-vs-host disease across major histocompatibility barriers: requirement for leucyl-leucine methyl ester sensitive cytotoxic T cells. , 1987, Journal of immunology.

[22]  A. Hess,et al.  Graft‐versus‐Host Reactions and Disease , 1985, Immunological reviews.

[23]  B. Hamilton.  ABSENCE OF CORRELATION BETWEEN CYTOLYTIC T LYMPHOCYTES AND LETHAL MURINE GRAFT‐VERSUS-HOST DISEASE IN RESPONSE TO MINOR HISTOCOMPATIBILITY ANTIGENS , 1984, Transplantation.

[24]  H. Morse,et al.  Dissociation of severe lupus-like disease from polyclonal B cell activation and IL 2 deficiency in C3H-lpr/lpr mice. , 1984, Journal of immunology.

[25]  P. Kincade,et al.  Preferential but Nonexclusive Expression of Macromolecular Antigens on B‐Lineage Cells , 1983, Immunological reviews.

[26]  G. McDonald,et al.  The fine structure of human rectal epithelium in acute graft‐versus‐host disease , 1982, The American journal of surgical pathology.

[27]  G. Janossy,et al.  USE OF ANTI-T-CELL MONOCLONAL ANTIBODY OKT3 TO PREVENT ACUTE GRAFT-VERSUS-HOST DISEASE IN ALLOGENEIC BONE-MARROW TRANSPLANTATION FOR ACUTE LEUKAEMIA , 1982, The Lancet.

[28]  J. Boitnott,et al.  Pathology of the liver with bone marrow transplantation. Effects of busulfan, carmustine, acute graft-versus-host disease, and cytomegalovirus infection. , 1980, The American journal of pathology.

[29]  G. Sale,et al.  The ultrastructure of the human epidermis in chronic graft-versus-host disease. , 1979, The American journal of pathology.

[30]  J. Sprent,et al.  Lethal graft-versus-host disease after bone marrow transplantation across minor histocompatibility barriers in mice. Prevention by removing mature T cells from marrow , 1978, The Journal of experimental medicine.

[31]  W. Elkins.  Correlation of graft-versus-host mortality and positive CML assay in the mouse. , 1976, Transplantation proceedings.

[32]  R. Storb,et al.  Histopathology of graft-vs.-host reaction (GvHR) in human recipients of marrow from HL-A-matched sibling donors. , 1974, Transplantation proceedings.

[33]  M. Jadus,et al.  The role of cytokines in graft-versus-host reactions and disease. , 1992, Bone marrow transplantation.

[34]  R. Eisenberg,et al.  Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. , 1991, Annual review of immunology.

[35]  R. Storb,et al.  Human marrow transplantation: an immunological perspective. , 1987, Advances in immunology.