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R J Fischel

Publications and source records attributed to R J Fischel.

At least 37 records · Page 2Linked to original sources
PubMed1992

Mechanism of complement activation in the hyperacute rejection of porcine organs transplanted into primate recipients.

The authors investigated the importance of natural antibody and complement in the pathogenesis of hyperacute xenograft rejection using in vivo and in vitro pig to primate models. Studies were carried out in rhesus monkeys transplanted with a pig heart or kidney in which hyperacute rejection was observed within a few hours. The rejected organs showed deposits of IgM, C3, C4, C5, and C9 neoantigen along small blood vessels, but few deposits of factors B and P. Removal of anti-endothelial cell "natural" antibodies by plasmapheresis, immunoabsorption, and immunosuppression techniques resulted in marked prolongation of the survival of a subsequently transplanted heart, even when complement levels were within the normal range. Thus, complement, in the absence of natural antibodies, did not initiate hyperacute rejection in this species combination. The requirements for complement activation in human serum to cause cytotoxicity of porcine endothelial cells were then evaluated. Cytotoxicity was abrogated by depleting human serum of IgM, C2, or C5, but not of factor B. Restoration of the effect of serum on endothelial cells was achieved by reconstitution of the respective depleted sera with purified IgM or with the corresponding complement proteins, indicating that IgM and the classical, but not the alternative, pathway of complement, were involved. Identical conclusions were drawn from experiments to ascertain the requirements for complement activation in human serum to mediate binding of iC3b to porcine endothelial cells. The authors conclude that in a pig to primate xenograft complement does not directly initiate injury to the graft but rather requires activation by bound xenoreactive natural antibodies; IgM antibodies directed against endothelial cells activate the classical complement pathway, which then contributes to endothelial cell activation and subsequent events characteristic of hyperacute rejection.

Animals↗
PubMed1991

Long-term outlook for renal transplant recipients with one-year function. "Doctor, what are my chances"?

Patients with renal transplants that survive the first year often ask about the chance of long-term function. We studied 1850 patients with primary transplants from June 7, 1963 to September 1, 1988 who had graft survival of greater than 1 year. Patients were grouped by donor type, diabetic status, and whether or not they received cyclosporine (CsA). Half-life (T1/2) was used to compare long-term survival rates. We determined the long-term graft survival inclusive and exclusive of death with function (DwF) in order to study all patients and to direct attention to immunologic losses. Pre-CsA, DwF was the major cause of graft loss in each cohort. Cause of DwF was cardiovascular (49%), infection (26%), and cancer (14%). The percentage of patients experiencing DwF was much higher in the pre-CsA group vs. the CsA group: HLA-identical living related donor, 16% vs. 3%; non-HLA-identical LRD, 22% vs. 5%; and cadaver donors, 26% vs. 11%. T1/2 for 711 transplants to diabetics (DM) was 9.01 +/- .54 years, while for transplants to 1139 nondiabetics (NDM) T1/2 was 13.57 +/- .68 (P less than .05). When DwF is excluded (DwFex) DM T1/2 = 23.5 +/- 2.69 and NDM T1/2 = 22.2 +/- 1.55 (NS). Overall, for HLA-identical transplants (n = 297) T1/2 = 26.13 +/- 3.35 and DwFex T1/2 = 104.3 +/- 28.93. Nonidentical LRD (n = 845) T1/2 = 11.25 +/- .61 and DwFex T1/2 = 19.37 +/- 1.55. For CAD (n = 701) T1/2 = 9.10 +/- .54 and DwFex T1/2 = 17.49 +/- 1.65. Comparing pre- and post-CsA cohorts, CsA has not resulted in significant improvement in long-term graft survival by T1/2 analysis with DwFex. It appears that overall long-term graft survival has improved with the introduction of CsA. Much of the improvement may be attributed to better first year graft survival and a reduction in cases of DwF. DM patients have an equal opportunity for long-term graft survival if they do not die from other causes. Excluding DwF, especially as an older population is transplanted, is important in determining chances of immunologic loss. Use of this type of analysis suggests that long-term outlook for 1-year graft survivors is excellent.

Cyclosporins↗
PubMed1991

Immunopathology of hyperacute xenograft rejection in a swine-to-primate model.

Hyperacute rejection is the inevitable consequence of the transplantation of vascularized organs between phylogenetically distant species. The nature of the incompatibility and the pathogenetic mechanisms that lead to hyperacute xenograft rejection are incompletely understood. We investigated these issues by the immunopathological analysis of tissues from swine renal and cardiac xenografts placed in rhesus monkeys. Hyperacute rejection was associated with deposition of recipient IgM and classic but not alternative complement pathway components along endothelial surfaces, the formation of platelet and fibrin thrombi, and the infiltration of neutrophils. In animals from which natural antibody was temporarily depleted by organ perfusion, rejection was observed at 3 days to 5 days posttransplant. The immunopathology of rejection in these tissues revealed focal vascular changes similar to those observed in hyperacute rejection. A xenograft functioning for a prolonged period in a recipient temporarily depleted of circulating natural antibody contained recipient IgM along endothelial surfaces but no evidence for significant deposition of complement, formation of platelet and fibrin thrombi, or infiltration of neutrophils. These results suggest that rhesus IgM contributes significantly to the development of hyperacute rejection in the swine to Rhesus model and that the fixation of complement is a critical factor in the recruitment of the coagulation cascade and platelet aggregation--and possibly in the adherence and infiltration of PMN.

Animals↗
PubMed1990

Cardiac transplantation.

With the advent of cyclosporine and triple-drug therapy, cardiac transplantation has developed from a curiosity into an effective therapy. Optimal results require proper recipient selection, careful donor identification and preparation, and skillful surgical and postoperative care. Recent trends to expand the donor and recipient pools will result in an amplification of the problems encountered to date. Causes of significant perioperative morbidity and mortality continue to be graft failure, infection, and rejection. Careful attention to elevated recipient pulmonary vascular resistance and donor heart preservation are essential to prevent graft failure. Diagnosis and treatment of infection and rejection depend on anticipation and vigilance by the cardiac transplant team. Knowledge of and familiarity with immunosuppressive regimens and the inherent side effects, both unique to each drug and common to the group, should enable minimization of the drugs' toxicities. Long-term sequelae of cardiac transplantation are now being defined and our ability to affect them is a continuing challenge. Cardiac transplantation has become a safe and effective treatment for end-stage cardiovascular disease. Success is now measured, not by patient survival, but by the quality of life achieved by those who receive this treatment modality.

Critical Care↗