Platt, Jeffrey L.

The National Heart, Lung, and Blood Institute (NHLBI) recently convened the Heart and Lung Xenotransplantation Working Group to identify hurdles to the clinical application of xenotransplantation, defined as the use of animal organs or tissue for transplantation, and to recommend possible solutions to these problems. The group consisted of experts in xenotransplantation from academia, industry, and federal agencies, and the discussions focused on those areas within the mission of the NHLBI. The areas covered included immunologic and physiological barriers to xenotransplantation, the limitations of the current animal models, the need for collaboration among groups, the high costs of studies using nonhuman primates and genetic engineering of pigs, and the unique problems of lung xenotransplantation. This report is a summary of those discussions.

The application of xenotransplantation faces daunting immunological hurdles, some of which might be overcome with the induction of tolerance. Porcine organs transplanted into primates are subject to several types of rejection responses. Hyperacute rejection mediated by naturally occurring xenoreactive antibodies and complement can be overcome without tolerance. Acute vascular rejection and cellular rejection, however, may present important opportunities for immunological tolerance, and humoral rejection might be approached by various mechanisms including (i) clonal deletion, (ii) anergy, (iii) immune deviation, (iv) induction of immunoregulatory or suppressor cells, or (v) veto cells. B-cell tolerance, useful for preventing humoral rejection, might be approached through clonal anergy. It remains to be determined, however, whether tolerance induction is required for xenotransplantation and by which means the various mechanisms of tolerance can be applied in the setting of xenotransplantation. Regardless, the study of tolerance will surely expand understanding of the physiology and pathophysiology of the immune system.

ABSTRACT Although immune responses are generally considered to be systemic, local events such as interaction of complement products with blood vessels and with inflammatory cells play a pivotal role in determining the nature and manifestations of immune responses. This paper will discuss how blood vessel physiology and immunity influence one another to reach homeostasis upon exposure to an infectious agent. We review new insights into the mechanisms by which the microenvironment of tissues protects against microbial invasion yet facilitates migration of leukocytes and ‘decides’ whether immunity or tolerance ensues and whether, in the face of immunity, protective responses or tissue injury ensues. These ‘decisions’ are made based on interaction of components of normal tissues such as proteoglycans and injured tissues such as cell‐associated cytokines with receptors on immune cells and blood vessels.—Saadi, S., Wrenshall, L. E., Platt, J. L. Regional manifestations and control of the immune system. FASEB J. 16, 849–856 (2002)