TART in prepubertal males with classic CAH could be found during childhood. We also report differences in markers of gonadal function in a subgroup of patients, especially in those with inadequate control.

We have come a long way in our understanding of antibodies as effectors of liver graft damage, but we still have much to learn. Animal heterografts provided the first evidence that livers are susceptible to antibody-mediated damage. The pathophysiologic events are similar to those of extrahepatic organ grafts, but the liver is relatively resistant and rapidity of graft destruction is slower, if it occurs at all. Nevertheless, the ABO isoagglutinins can predictably cause human liver allograft failure, often in a quickened, but rarely a hyperacute fashion. The liver is more resistant to lymphocytotoxins, and in many cases will suffer no apparent damage. However, when present, a spectrum of graft pathologic changes can be seen. Early manifestations include hemorrhagic necrosis and lesions mimicking "preservation" injury. Later on, ischemic biliary necrosis and small bile duct loss may be seen. The variability is likely related to a balance between destructive antibody class, specificity, and titers and the ability of the liver to withstand the assault. More precise characterization of lymphocytotoxic antibodies is needed in clinical practice. In addition, antigen distribution in the graft, release of soluble MHC antigens, the role of Kupffer cells and other mechanisms of liver resistance are likely areas of fruitful investigation.

Heterotopic hamster hearts transplanted to unmodified LEW rats underwent humoral rejection in 3 days. Survival was prolonged to a median of 4 days with 2 mg/kg/day FK506. As monotherapy, 15 mg/kg/day cyclophosphamide greatly prolonged graft survival--far more than could be accomplished with RS-61443, brequinar (BQR), mizoribine, methotrexate, or deoxyspergualin. However, when FK506 treatment, which was ineffective alone, was combined with a short induction course (14 or 30 days) of subtherapeutic BQR, RS-61443, or cyclophosphamide, routine survival of heart xenografts was possible for as long as the daily FK506 was continued. In addition, a single large dose of 80 mg/kg cyclophosphamide 10 days preoperatively allowed routine cardiac xenograft survival under FK506. The ability of these antimetabolites to unmask the therapeutic potential of FK506 correlated, although imperfectly, with the prevention of rises of preformed heterospecific cytotoxic antibodies immediately postoperatively. As an adjunct to FK506, azathioprine was of marginal value, whereas mizoribine, methotrexate, and deoxyspergualin (DSPG) were of intermediate efficacy. After orthotopic hepatic xenotransplantation, the perioperative survival of the liver with its well-known resistance to antibodies was less dependent than the heart on the antimetabolite component of the combined drug therapy, but the unsatisfactory results with monotherapy of FK506, BQR, RS-61443, or cyclophosphamide were changed to routine success by combining continuous FK506 with a short course of any of the other drugs. Thus, by breaking down the antibody barrier to xenotransplantation with these so-called antiproliferative drugs, it has been possible with FK506 to transplant heart and liver xenografts with consistent long-term survival of healthy recipients.

No abstract

Background-In this study, using a murine model of aortic allotransplantation, the role of blockade of signaling through CD28/B7 and CD40/CD40 ligand co-stimulatory pathways in the evolvement of posttransplant vasculopathy was examined.