Financial aspects of organ procurement from deceased donors in the USA-Relevance to xenotransplantation.

When clinical xenotransplantation is introduced, the costs associated with acquisition of a genetically engineered pig organ are as yet unknown. How will these costs compare with those currently associated with the acquisition of deceased human organs? An understanding of the financial aspects of deceased organ and tissue procurement in the USA is therefore worthwhile. We have therefore attempted to review certain economic aspects of non-profit and for-profit organizations that provide cadaveric organs and/or tissues for purposes of transplantation into patients with end-stage organ failure, cellular deficiencies, or in need of reconstructive procedures. We briefly consider the laws, organizations, and business practices that govern the acquisition, processing, and/or distribution of cadaveric organs and tissues, and the economic implications of industry practices. In particular, we explore and highlight what we perceive as a lack of transparency and oversight with regard to financial practices, and we question whether donor families would be entirely happy with the business environment that has developed from their altruistic donations. Until xenotransplantation becomes established clinically, which will negate the need for any system of organ procurement and allocation, we suggest that those involved in organ and cell transplantation, as well as those who participate in reconstructive surgery, should take responsibility to ensure that the financial practices associated with procurement are transparent, and overseen/regulated by a responsible authority. We suggest the major transplant societies should take a lead in this respect. The ability to acquire a genetically engineered pig organ whenever required through a simple commercial transaction (as in the acquisition of a life-saving drug) will be greatly to the patient's benefit.

Therapeutic regulation of systemic inflammation in xenograft recipients.

Inflammation is known to preclude tolerance after transplantation. We have previously shown that systemic inflammation in xenograft recipients (SIXR) precedes activation of coagulation in the absence of T cell responses. Accordingly, SIXR may amplify innate and adaptive immune responses against xenografts after pig-to-primate xenotransplantation, even with efficient immunosuppressive therapy. We evaluated the impact of anti-inflammatory agents on pro-inflammatory cytokines and chemokines in pig artery patch and heart xenograft recipients. Baboons received an artery patch (Group1, n=8) or heart (Group2, n=4) from genetically engineered pigs. All baboons received lymphodepletion with thymoglobulin (ATG) and costimulation blockade-based immunosuppression (anti-CD40 and/or CTLA4Ig). In Group1, baboons received either (i) no anti-inflammatory agents (n=2), (ii) cobra venom factor (CVF, n=2), (iii) α1-antitrypsin (AAT, n=2), or (iv) interleukin (IL)-6 receptor antagonist (IL-6RA, n=2). In Group2, all baboon received corticosteroids, either without (n=2) or with (n=2) IL-6RA. Serum IFN-γ, TNF-α, IL-1ß, IL-17, IL-6, IL-8, MCP-1, and sCD40L levels were measured by Luminex. Fibrinogen, D-dimers, and C-reactive protein (C-RP) were also measured. Recipient baboon T cell proliferation was evaluated by mixed lymphocyte reaction (MLR) before and after transplantation. Pig and baboon tissue factor (TF) mRNA levels in heart xenografts were measured by RT-PCR. In no recipient was a marked increase in T cell response to pig cells observed after transplantation. In Groups 1 and 2, post-transplantation levels of IFN-γ, TNF-α, IL-1ß, and IL-17 remained comparable to or lower than pre-transplant levels, except in one heart recipient that succumbed to CMV infection. In Group1, when no anti-inflammatory agent was administered, post-transplant levels of IL-6, IL-8, and MCP-1 were elevated. After CVF, IL-6, IL-8, and MCP-1 remained low. After IL-6RA, IL-6 and MCP-1 were elevated. After AAT, IL-8 was elevated. sCD40L became elevated intermittently in most recipients irrespective of the administered anti-inflammatory agent. In Group2, IL-6 was transiently elevated, particularly after IL-6RA administration. MCP-1 gradually increased by 2 months in Group2 recipients. sCD40L generally remained low except in one recipient. In Group1 and Group2 recipients, C-RP levels were elevated except after IL-6RA administration, while D-dimers were elevated regardless of administration of anti-inflammatory agent. In Group2, pig TF mRNA levels were increased in heart xenografts compared to naive pig hearts, irrespective of IL-6 receptor antagonist administration. Additionally, baboon TF mRNA levels were detectable in heart xenografts, but not in naive pig hearts. Some pro-inflammatory cytokines and chemokines are elevated in xenograft recipients, even with efficient T cell-directed immunosuppressive therapy. Persistent elevation of D-dimers, and individual cytokines and chemokines suggest a continuous inflammatory response, despite administration of anti-inflammatory agents. Systemic administration of combined anti-inflammatory agents as well as complement regulation may be essential to prevent SIXR after xenotransplantation.