Evaluation of innate immune activation after ex vivo xenoperfusion of GTKO/Hcd46/HLA-E transgenic pig hearts with human blood

EARLY MORNING SYMPOSIUM 2 THURSDAY, SEPTEMBER 21 – 07:00 TO 08:00 MS.2. 2 | Is sensitization to pig antigens detrimental to subsequent allotransplantation? David K.C. Cooper1; Qi Li1; Liaoran Wang1; Hidetaka Hara1 1Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham Alabama, United States Introduction: An important question in xenotransplantation (XTx) that has not yet been definitively answered is whether an allotransplant can safely be carried out in a patient who has become sensitized to a previous pig xenograft. In other words, do elicited antipig antibodies crossreact with alloantigens? We have searched the literature in an effort to answer this question, and identified only 10 studies of some relevance. Experimental xenotransplantation: Three groups provided evidence to suggest that primary monkey xenografts did not seem to induce humoral or cellmediated immune responses that jeopardized the survival of a secondary baboon allograft. One of these groups (in 1995) also investigated whether exposure to pig organs was detrimental to a subsequent allograft. No baboon that had received a pig graft developed antibodies to alloantigens. In 3 pig graft recipients, secondary baboon organ allotransplantation was carried out without an incidence of any form of antibodymediated or accelerated cellular rejection. In a 2004 in vitro study, Baertschiger demonstrated an absence of humoral and cellular alloreactivity in baboons sensitized to pig antigens, as did Key (2004) in a pigtomonkey kidney XTx model. In a pigtomonkey decellularized corneal XTx model, Choi (2014) reported no increase in the antibody or T cell responses to monkey antigens. Following pigtobaboon skin XTx, Albritton (2014) also reported no increases in the antibody or T cell response to alloantigens. Kim (2016) transplanted pig islets into mice without evidence of an increased immune response to mouse antigens. Clinical xenotransplantation: Both clinical studies related to bridging a patient in hepatic failure to liver allotransplantation. In 1999, Baquerizo provided data to show that patients bridged by a bioartificial liver (BAL), that incorporated pig hepatocytes, could subsequently undergo successful liver allotransplantation. Levy (2000) bridged two patients by extracorporeal blood perfusion through livers from pigs transgenic for hCD55/hCD59. Both subsequent liver allotransplants were successful. Conclusions: Although the data we were able to find were obtained from various experimental models, not all of which may be directly relevant to pig organ transplantation in human recipients, and from clinical studies in which exposure to pig antigens was relatively brief, they suggest that crossreactive antibodies do not develop and that there is no evidence of antibodymediated or accelerated cellular rejection of a subsequent allograft. We conclude that there is to date no convincing evidence that an initial pig xenograft is detrimental to a subsequent allograft. STATEOFTHEART SESSION 1 THURSDAY, SEPTEMBER 21 – 08:00 TO 09:10 SOTA.1. 2 | Heart xenotransplantation Muhammad Mohiuddin1 1University of Maryland Baltimore, Baltimore, MD, United States Despite the efforts to avert heart disease by adopting preventive measures, using medicine to control the triggering factors like hypercholesterolemia and hypertension, and utilizing improved methods of minimally invasive and surgical interventions to treat cardiac disease, a significant number of population around the world will still undergo end stage organ failure that will require heart transplantation. All surveys indicate that the number for patients with end stage heart disease is not reducing and mortality is increasing among these patients due to paucity of donor organs. Mechanical assist devices are helpful in these conditions and have improved over time but are still far from being perfect and are not free from lethal complications. In such dismal circumstances, using a nonhuman heart to save these precious lives seems very appropriate. Until recently, the survival results for cardiac xenografts in large animal models have not been encouraging and available measures to control rejection had failed. However, in last few years, new techniques of genetic modifications of donor organs and use of novel immunomodulatory drugs have remarkably improved the graft survival in experimental heterotopic cardiac xenograft models. In this presentation, I will discuss the possible role of individual genetic modifications in averting cardiac xenograft rejection and highlight a critical role played by the novel immunomodulatory agents. Experimental results using the preclinical model of orthotopic cardiac xenograft survival have not been the same as seen in the herterotopic models. Here I will highlight some of the known reasons of these subpar results. In addition, I will discuss some of the possible solutions to overcome the remaining hurdles in the orthotopic model to help this life saving technique become a clinical reality.