L. Bühler, T. Friedman, J. Iacomini, D.K.C. Cooper

Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, USA.

TABLE OF CONTENTS

1. Abstract

2. Introduction

3. Concordant and discordant xenotransplantation

3.1. Definitions
3.2. Pathogenesis of xenograft rejection

3.2.1. Hyperacute rejection
3.2.2. Acute vascular rejection
3.2.3. Acute cellular rejection
3.2.4. Chronic rejection

4. Choice of animal organ donor for human patients

5. Experimental methods of prolonging survival of discordant xenografts

5.1. Anti-pig antibody depletion or inhibition
5.2. Complement depletion or inhibition
5.3. The genetically engineered pig

5.3.1. Expression of human complement-regulatory proteins
5.3.2. a gal 'knockout'
5.3.3. Competitive glycosylation

5.4. Tolerance to donor species by molecular chimerism

5.5. Tolerance to donor species by mixed hematopoietic cell chimerism

6. Experimental and clinical progress in the xenotransplantation of tissues and cells

7. Discussion

8. References

1. ABSTRACT

Organ transplantation is limited by the number of cadaveric human donor organs that become available. Xenotransplantation - the transplantation of organs and tissues between animal species - would supply an unlimited number of organs and offer many other advantages. The pig has been identified as the most suitable donor animal. Pig organs, when transplanted into humans or nonhuman primates, are, however, rejected hyperacutely within minutes by antibody-mediated complement activation. Human anti-pig antibodies have been identified as being directed against galactose a 1-3galactose (a Gal) epitopes on pig vascular endothelium. Methods have been successfully developed to prevent hyperacute rejection. These include (i) depletion or inhibition of recipient antibodies or complement and (ii) development of transgenic pigs that express a human complement-regulatory protein (e.g. hDAF). The persistence or return of anti-pig antibody, however, even following the use of hDAF pig organs, eventually leads to what has been variously termed "acute vascular rejection" or "delayed xenograft rejection", which is again believed to be largely antibody-dependent. Nevertheless, experimental pig-to-primate organ xenotransplantation now results in transplant function for days and weeks rather than minutes. Little is yet known of the nature of the acute cellular rejection response that is anticipated to follow, and of any subsequent chronic rejection that may develop. Tolerance to both the a Gal epitope and to swine leukocyte antigens (SLA) is being explored using gene therapy techniques and by the induction of hematopoietic cell chimerism. The development of genetically engineered pigs that do not express the a Gal epitope is also being pursued. Considerable progress has been made in recent years, but experimental results do not yet warrant the initiation of a clinical trial of organ xenotransplantation. However, trials are already underway of pig cell transplants in patients with diabetes and neurodegenerative conditions, such as Parkinson's disease.