Evidence against a pivotal role of preformed antibodies in delayed rejection of a guinea pig-to-rat heart xenograft.

INTRODUCTION: Whereas the involvement of elicited xenoantibodies in delayed xenograft rejection is currently being substantiated, this study focuses on the role of the preformed fraction of xenoantibodies. METHODS: To check the influence of the latter, we combined pretransplant complement inactivation (cobra venom factor) and antibody reduction (plasmapheresis) in a guinea pig-to-rat heart transplant model. RESULTS: Antibody reduction on plasmapheresis before xenografting did not prolong delayed xenorejection in decomplemented rats, although the immunohistologic pattern lacked the immunoglobulin deposits along endothelial walls found in xenografts of merely decomplemented recipients. Astonishingly, plasmapheresis, if carried out 2 days before transplantation, almost tripled xenograft survival, although preformed antibody levels were completely restored and even rebounding at the time of grafting. The pattern and number of infiltrating cells did not differ in dependence of the timing of plasmapheresis nor did the proliferative response of lymphocytes in the mixed lymphocyte reaction differ. However, plasmapheresis led to a retarded decrease of the mononuclear cell tumor necrosis factor alpha secretory potential, which correlated well with a diminished immunohistologic staining of tumor necrosis factor alpha secreted by graft-infiltrating mononuclear cells. CONCLUSION: These findings argue against a pivotal role of preformed xenoantibodies in the pathomechanistic process of delayed xenograft rejection and challenge the therapeutic strategy to reduce preformed xenoantibody levels before xenotransplantation in complement-inactivated recipients.

[Immunosuppression by parenteral lipid emulsions in a model of defined immunostimulation]. / Inmunosupresión de las emulsiones lipídicas parenterales en un modelo de inmunoestimulación definida.

The immunosuppressive effect of intravenous fat emulsions with different n-3/n-6 fatty acid ratio was studied in the heterotopic rat heart allotransplant model. Twenty percent emulsions of safflower oil (n-3/n-6 = 1/370), fish oil (7.6/1), soybean oil (1/6.5) and a 1:1 mixture of safflower and fish oil (1/2, 1; oil control group) were continuously infused (9 g fat/Kg b.w./day; n = 10 each group) after transplantation until rejection. Graft survival time, subpopulations of infiltrating and circulating immunocompetent cells and Interleukin-6 release of circulating monocytes were analyzed. In the safflower oil, fish oil and soybean oil groups graft survival was prolonged to 13.3, 12.3 and 10.4 days vs. 6.7 days in the oil control group and 7.8 days in the saline control group (p < 0.01). In the two groups with the highest prolongation of graft survival the number of infiltrating cells was reduced by up to 50 percent and the peripheral blood monocyte interleukin-6 release by up to 45 percent. Beyond that, circulating T-cells were reduced in the fish oil group. Intravenous fat emulsions show a varying immunomodulatory effect in dependence of the n-3/n-6 fatty acid ratio. Both n-6 and n-3 fatty acids, if applied as main fatty acid source, exert immunosuppressive effects by a diminished infiltration, mobilisation and cytokine release of immunocompetent cells. Soybean oil with a more balanced n-3/n-6 fatty acid ratio than safflower is significantly less immunosuppressive than safflower oil and fat emulsions with a n-3/n-6 fatty acid ratio of 1/2 are immunologically neutral.