The success of clinical transplantation is one of modern medicine's hallmark achievements. Unfortunately, a severe shortage of human organs, cells, and tissues constrains application of this life-saving technology. This RFA recognizes the potential for transplants from another species to humans (xenotransplantation) to fulfill the fields potential. For scientific and ethical reasons, a consensus has formed around discerning how to safely use pig organs for this purpose. Clinical application of pig-to-human xenografts is currently prevented by vigorous immunologic barriers. Major progress has been made over the past two decades to understand and overcome these barriers, with key contributions over the past 9 years from our Program and other NIAID Consortium members. Most importantly, our Program has produced pigs that express a large number of human proteins that each protects the pig organ from injury by the primate immune response. The lung xeno model has been particularly useful to demonstrate the value of each of these modifications, and to identify remaining problems. With a combination of three to six gene modifications to the pig, and a carefully tailored drug treatment regimen to the recipient, current results have advanced from minutes to hours (lung) or days (liver), with more significant progress for kidneys (from weeks to months) and hearts, where survivals past one and even two years have recently been accomplished by members of our consortium. Our proposals in response to the current RFA concentrate attention largely on the residual problem of the inflammatory response to pig organs. We shall explore methods of preventing or suppressing this response through either novel pig genetics or pharmacologic interventions. We will investigate transplantation of organs from these novel pigs, modifications to our already successful immunosuppressive regimen (in an effort to minimize infectious complications), and several anti-inflammatory agents that might allow consistent long-term (>6 months) pig kidney and heart graft survival, while significantly extending survival of livers and lungs. These studies will be carried out in our established kidney (Pittsburgh), heart (NHLBI), liver and lung (Maryland) models, with all of which we have many years' experience and expertise. The outcomes of our studies will be comprehensively evaluated by numerous laboratory assays, with all of which we have experience at one or more of our participating centers. We hypothesize that, within the 5-year funding period, this will enable consideration to be given to clinical trials of pig kidney, heart, and liver transplantation and will improve lung survival markedly.
There is a critical shortage of organs from deceased humans for purposes of transplantation. The proposed studies are directed towards resolving this problem by exploring and overcoming the remaining barriers that currently prevent pig organs from being transplanted successfully into patients with end-stage organ (heart, kidney, lung, liver) failure. It is anticipated that these barriers can be overcome by the use of organs from unique genetically-engineered pigs and novel reagents. Project 1: Prolonging life-supported pig kidney and heart graft survival in baboons by suppressing inflammation Project Leader (PL): Cooper, D. DESCRIPTION (provided by applicant): Experimental xenotransplantation (xenoTx), in the form of pig organ transplantation (Tx) in nonhuman primates, has made major advances during the past 10 years since this NIAID funding mechanism was introduced. The problems of early immune rejection and coagulation dysregulation have been greatly reduced, but there is increasing evidence that an inflammatory response may be activating the immune system and/or amplifying coagulation dysfunction. The overall hypothesis that will be investigated in Project 1 is that an inflammatory response plays a significant role in pig kidney and heart graft failure after Tx into baboons, and that its prevention or suppression will result in prolonged graf survival. The mechanisms whereby anti-inflammatory agents prolong graft survival, e.g., by reducing the innate or adaptive immune response, or by minimizing coagulation dysfunction, will be comprehensively investigated. The current proposal will therefore aim to confirm that the combination of (i) unique multi-gene pigs (i.e., pigs with 6 or 7 genetic modifications to protect their tissues from the primate immune response and from the effects of coagulation dysregulation), (ii) an effective immunosuppressive (IS) regimen, and (iii) a targeted anti-inflammatory regimen will, together, allow consistent function of life-supporting pig kidneys and hearts for >6 months in the absence of rejection or coagulopathy. In Aim 1 (investigated in Pittsburgh), we will explore the effect of selected anti-inflammatory agents on life-supporting kidney graft survival in baboons receiving kidneys from multi-gene pigs and using the proven IS regimen (developed during the present 5-year funding period). If the expected outcome is not consistently achieved, we will transplant kidneys from pigs (available to us in 2016-17) expressing different / additional transgenes that might prove advantageous. In Aim 2 (NHLBI), in the heterotopic (non-life-supporting) heart Tx model we shall investigate whether all components of the previously successful IS regimen are essential or whether, after the Tx of a heart from a multi-gene pig (+/- an effective anti-inflammatory regimen), the IS regimen can be minimized, or anticoagulation omitted, thus reducing the risks of long-term therapy, e.g., opportunistic infection or bleeding. Promising approaches will be evaluated in a life-supporting orthotopic model. The proposed studies are innovative in several respects - (i) unique novel multi-gene pigs, (ii) the subsequent availability of further pigs with possibly advantageous genetic manipulations, (iii) investigation of the role of the inflammatory response in xenoTx. Success in the proposed studies would enable clinical trials of kidney and heart xenoTx as a first step to eliminate current reliance on deceased human organs, making organ Tx available to a greatly expanded number of patients.
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