Synthetic MHC class I peptide prolongs cardiac survival and attenuates transplant arteriosclerosis in the Lewis-->Fischer 344 model of chronic allograft rejection.

BACKGROUND A synthetic peptide corresponding to residues 75-84 of the alpha1 domain of HLA-B7 molecule (HLA-B7.75-84 [Allotrap]) inhibits cytotoxic T cell function in vitro and, when combined with subtherapeutic doses of cyclosporine (CsA), prolongs allogeneic cardiac survival. We now report the effects of HLA-B7.75-84 in the Lewis --> Fischer 344 rat model of chronic cardiac allograft rejection. METHODS Animals were treated with CsA (5 mg/kg/day s.c.) alone or with CsA plus alternate-day HLA-B7.75-84 (20 mg/kg/day i.p.) for 30 days. Allografts harvested at day 100 were evaluated by histology and immunohistology. RESULTS HLA-B7.75-84 plus CsA prolonged allograft survival (75% of allografts survived >90 days) compared with CsA alone (27% of allografts survived >90 days) (P<0.05). Histologic examination of control allografts showed dense cellular infiltrates and moderate transplant arteriosclerosis (>75% of arteries showed 10-20% occlusion). Infiltrating leukocytes consisted of macrophages (>75% cells), T cells (10-20%), and rare natural killer cells (<5%). Cell activation was shown by expression of major histocompatibility complex class II antigens (>75%), interleukin (IL) 2 receptor (5-10%), and staining for IL-2 (approximately 5% of intragraft mononuclear cells), interferon-gamma (5-10%) and tumor necrosis factor-alpha (approximately 20%). Leukocytes and vessels also showed labeling for the fibrogenic cytokine, transforming growth factor-beta, and all vessels showed dense deposition of IgG (IgG2a, IgG2b) and C3. The addition of HLA-B7.75-84 decreased overall cellularity (P<0.01) without affecting the composition of the infiltrate, but completely prevented transplant arteriosclerosis, diminished myocardial injury, and abrogated expression of IL-2R, IL-2, interferon-gamma, tumor necrosis factor-alpha, and transforming growth factor-beta. HLA-B7.75-84 also blunted the humoral response, which resulted in a predominance of vascular deposition of the non-complement-fixing IgG2c isotype and a concomitant decrease in C3. CONCLUSIONS Therapy with synthetic class I major histocompatibility complex peptide (HLA-B7.75-84) attenuates key histologic features of graft arteriosclerosis, in association with inhibition of multiple cytokines and growth factors and modulation of host alloantibody responses in vivo, which is of interest since Allotrap is currently undergoing clinical trials.

[1]  D. Candinas,et al.  Accommodation of vascularized xenografts: Expression of “protective genes” by donor endothelial cells in a host Th2 cytokine environment , 1997, Nature Medicine.

[2]  J. Fechner,et al.  Immunosuppressive effects of an HLA class I-derived peptide in a rat cardiac allograft model. , 1996, Transplantation.

[3]  M. Sayegh,et al.  Chronic cardiac rejection in the LEW to F344 rat model. Blockade of CD28-B7 costimulation by CTLA4Ig modulates T cell and macrophage activation and attenuates arteriosclerosis. , 1996, The Journal of clinical investigation.

[4]  J. Drazen,et al.  Sorting out the cytokines of asthma , 1996, The Journal of experimental medicine.

[5]  L. Gao,et al.  A synthetic dimeric HLA class I peptide inhibits T cell activity in vitro and prolongs allogeneic heart graft survival in a mouse model. , 1995, Transplantation.

[6]  L. Paul.  Chronic renal transplant loss. , 1995, Kidney international.

[7]  S. Ménoret,et al.  Prolongation of allogeneic heart graft survival in rats by administration of a peptide (a.a. 75-84) from the alpha 1 helix of the first domain of HLA-B7 01. , 1995, Transplantation.

[8]  C. Clayberger,et al.  Prolongation of skin allograft survival in mice following administration of ALLOTRAP. , 1995, Transplantation.

[9]  S. Tullius,et al.  Both alloantigen-dependent and -independent factors influence chronic allograft rejection. , 1995, Transplantation.

[10]  D. Adams,et al.  CD4+ mononuclear cells induce cytokine expression, vascular smooth muscle cell proliferation, and arterial occlusion after endothelial injury. , 1994, The American journal of pathology.

[11]  L. Tian,et al.  Rapamycin inhibits production of cytotoxic but not noncytotoxic antibodies and preferentially activates T helper 2 cells that mediate long-term survival of heart allografts in rats. , 1994, Journal of immunology.

[12]  T. Hostetter.  Chronic transplant rejection. , 1994, Kidney international.

[13]  R. Guttmann,et al.  Evidence that recipient CD8+ T cell depletion does not alter development of chronic vascular rejection in a rat heart allograft model. , 1994, Transplantation.

[14]  A. Krensky,et al.  Induction of allograft tolerance in rats by an HLA class-I-derived peptide and cyclosporine A. , 1994, Journal of immunology.

[15]  W. Baldwin,et al.  CYTOKINES, ADHESION MOLECULES, AND THE PATHOGENESIS OF CHRONIC REJECTION OF RAT RENAL ALLOGRAFTS , 1993, Transplantation.

[16]  B. Fellström,et al.  Chronic vascular rejection of the heart and the kidney--have rational treatment options emerged? , 1992, Transplantation.

[17]  P. Parham,et al.  Inhibition of alloreactive cytotoxic T lymphocytes by peptides from the α2 domain of HLA–A2 , 1987, Nature.

[18]  A. Krensky,et al.  Peptides corresponding to T-cell receptor-HLA contact regions inhibit class I-restricted immune responses. , 1993, Transplantation proceedings.

[19]  P. Parham,et al.  HLA-A2 peptides can regulate cytolysis by human allogeneic T lymphocytes , 1987, Nature.