Differential regulation of rejection of small intestinal and skin allografts in rats by injection of antibodies to ICAM-1 or the integrins alpha 4, alpha L, or beta 2.
Female Lewis (LEW) rats received orthotopic small intestinal transplantation (SIT), or tail skin grafts from female (Lewis x Brown Norway)F1 (LBNF1) rats, along with peritransplant portal venous (pv) infusion of LBNF1 bone marrow-derived dendritic cells derived from male donors. All animals received im injection with cyclosporin A (5 mg/kg) for 3 consecutive days following transplantation. In some cases rats received intravenous injections, at 2-day intervals, with 1 mg of monoclonal antibodies to ICAM-1 or the integrins alpha 4, alpha L, or beta 2, or combinations of these reagents. Cells were harvested from the recipient rats at different times posttransplantation, and single cell suspensions were analyzed by FACS for expression of CD3+, CD4+, CD8+, alpha beta TcR+, and gamma delta TcR+ cells. Other tissue samples were used for histopathological assessment of rejection. We also investigated donor-specific and third-party (Wistar-Furth, Wi) restimulation of host lymphocytes from MLN, PLN, and PP for production of different cytokines in vitro. Of the various antibodies tested, only anti-alpha 4, but not anti-alpha L, -beta 2, nor -ICAM-1 led to further increased graft survival of LBNF1 SIT beyond that seen with pv-infused cells alone (30 days vs 19 days), while the combination of anti-alpha L (or beta 2) and ICAM-1 produced further significantly increased survival of skin grafts (30 days vs 21 days). For both SIT and skin-grafted animals increased graft survival was associated with decreased production of IL-2 and IFN-gamma and increased production of IL-4 and IL-10 from tissues local to the graft (PP and draining LN, respectively), with less significant alterations in tissues distant to the graft (PLN for SIT, and MLN for skin grafts). While, as reported previously, pv-immunized SIT rats showed increased gamma delta TCR+ cells within the SIT in association with increased graft survival, treatment with anti-alpha 4 diminished this increase in gamma delta TCR+ cells, while simultaneously increasing SIT survival. Nevertheless, the bias toward increased IL-10 production, and decreased IFN-gamma production, from cells of animals showing increased survival was maintained. These data suggest that local graft infiltration with gamma delta TCR+ cells following pv immunization is not necessary for prolongation of survival in this model system, although functional changes in the local cytokines milieu may be important.
Gorczynski
R M
RM
Department of Surgery, University of Toronto Transplant Research, Ontario, Canada.
Fu
X M
XM
Issekutz
T
T
Cohen
Z
Z
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000502:physiology*; D018821:CD18 Antigens / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006084:Graft Rejection; D039441:Integrin alpha4; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D007421:Intestine, Small / Q000637:transplantation*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000502:physiology; D016038:Skin Transplantation / Q000276:immunology*; D014184:Transplantation, Homologous; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018821:CD18 Antigens; D016207:Cytokines; D016169:Lymphocyte Function-Associated Antigen-1; D016692:Receptors, Antigen, T-Cell, gamma-delta; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D039441:Integrin alpha4