Life-supporting pig-to-baboon renal transplantation using GalT knockout donors: Benefit of cotransplanting a vascularized donor thymic graft.
The use of animal organs for human transplantation could potentially alleviate the worldwide critical shortage of donor organs, and thus has stimulated investigation of novel strategies directed at making xenotransplantation applicable to the clinic. The latter will likely require overcoming barriers of rejection through strategies utilizing either immune suppression or tolerance induction, or a combination of the two. We have previously reported that vascularized donor thymic tissue grafts, transplanted either as composite thymokidneys or vascularized thymic lobe grafts, induced tolerance across fully allogeneic barriers in miniature swine. Recently, we have applied the strategy of vascularized thymic lobe transplantation in a model of hDAF pig-to-baboon xenotransplantation and demonstrated that these grafts induced donor-specific unresponsiveness for up to 2 to 3 months following transplantation, at which time the grafts were lost from apparent humoral rejection. We have now extended these studies using cloned alpha-1,3-galactosyltransferase (GalT) knockout pigs as donors. We report here our initial experience in a preclinical model of pig-to-baboon xenotransplantation. This abstract presents clinical data on recipients of GalT knockout kidneys, especially focusing on four long-term recipients of GalT knockout kidney plus thymus transplantation in detail. Briefly, these four baboons receiving either xeno-thymokidneys or vascularized thymic lobe plus kidney maintained longer than 2 months. Three of four long-term survivors maintained normal plasma creatinine levels for 56, 68, and 83 days, respectively, before expiring from unexpected causes (anesthetic complication during surgery to replace an infected intravenous catheter (day 68), and myocardial infarction, possibly drug-induced on days 56 and an arterial catheter trouble on day 83. Cytotoxic T-lymphocyte assays on day 78 in one long-term acceptor showed that the baboon maintained anti-allo cytotoxic T-lymphocyte responses but lost antipig cyctotoxic T-lymphocyte responses, indicating donor-specific unresponsiveness. The fourth baboon experienced an apparent rejection crisis between days 53 and 65, which reversed with anti-T-cell rejection therapy; subsequently the animal expired on day 81 from pneumonia. Neither hyperacute nor accelerated acute rejection was observed in any animal. Use of GalT knockout donors markedly extends the survival of vascularized thymus plus renal xenografts in baboons. Although the induction regimen still needs to be modified to reduce complications, these initial results are encouraging with regard to the potential of cotransplanting vascularized thymic tissue with organ xenografts as a means of achieving long-term tolerance across pig-to-primate barriers.[1]References
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