HUMORAL AND CELLULAR IMMUNOPATHOLOGY OF HEPATIC AND CARDIAC HAMSTER-INTO-RAT XENOGRAFT REJECTION - MARKED STIMULATION OF IGM++BRIGHT IGD+DULL SPLENIC B-CELLS/

Normal Lewis rat serum contains antibodies (IgM > IgG) that bind to ha mster leukocytes and endothelial cells. Transplantation of either the heart or liver from hamster rat results in release of hamster bematoly mphoid cells from the graft, which lodge in the recipient spleen (cell migration), where recipient T- and B-cell populations initiate DNA sy nthesis within one day. There is marked stimulation of splenic IgM++(b right)/IgD+(dull) B chaste in the marginal zone and red pulp, which ac count for 48% of tge total splenic blast cell population by 4 days aft er liver transplantation. CD4+ predominant T-cell proliferation in the splenic periarterial lymphatic sheath and paracortex of peripheral ly mph nodes occurs almost simultaneously. The effector phase of rejectio n in cardiac recipients is dominated by complement-fixing IgM antibodi es, which increase daily and result in graft destruction in 3 to 4 day s, even in animals treated with FK506. In liver recipients, combined a ntibody and cellular rejection, associated with graft infiltration by OX8+ natural killer, and fewer W3/25+ (CD4) lymphocytes, are responsib le for graft failure in untreated recipients at 6 to 7 days. FK506 inh ibits tge T-cell response in liver recipients and significantly prolon gs graft survival, but does not prevent the rise or deposition of IgM antibodies in the graft. However, a single injection of cyclophosphami de 10 days before transplantation effectively depletes the splenic IgM ++(bright)/IgD+(dull) cells and in combination with FK506, results in 100% survival of both cardiac and hepatic xenografts for more than 60 days. Although extrapolation of morphological findings to functional s ignificance is fraught with potential problems, we propose tge followi ng mechanisms of xenograft rejection. The reaction initially appears t o involve primitive host defense mechanisms, including an IgM-producin g subpopulation of splenic B cells and natural killer cells. Based on the reaction and distribution of OX8+ and W3/25+ cells, antibody-depen dent cell cytotoxicity and delayed-type hypersensitivity responses see m worthy of further investigation as possible effector mechanisms. Eff ective control of xenograft rejection is likely to require a dual phar maceutical approach, one to contain T-cell immunity and another to blu nt tge primitive B-cell response.