Background: There is a continuing critical shortage of organs from deceased human donors for transplantation, particularly for patients awaiting kidney transplantation. Efforts are being made to resolve the donor kidney shortage by the transplantation of kidneys from genetically-engineered pigs. Summary: This review outlines the pathobiological barriers to pig organ xenotransplantation in primates, which include (i) antibody-dependent complement-mediated rejection, (ii) a T cell-mediated elicited antibody and cellular response, (iii) coagulation dysregulation between pigs and primates, and (iv) a persistent inflammatory response. As a result of increasing genetic manipulation of the pig and the introduction of novel immunosuppressive agents, pig kidney graft survival has increased from minutes to months, and even to >1 year in some cases. Aspects of the selection of the patients for a first clinical trial are discussed. Although there would appear to be some cross-reactivity between anti-human leukocyte antigen (HLA) antibodies and swine leukocyte antigens expressed in pigs, some HLA-sensitized patients will be at no disadvantage if they receive a pig kidney. Furthermore, the current limited evidence is that, even if the patient becomes sensitized to pig antigens (after a pig organ transplant), this would not be detrimental to a subsequent allotransplant. The potential risk of infection with a pig microorganism, and the function of a pig kidney in a primate are also discussed. Key Message: The recent encouraging results of pig kidney transplantation in nonhuman primates suggest the likelihood of a successful (and safe) initial clinical trial, with graft survival for months or possibly years.

1.
Cooper DK. A brief history of cross-species organ transplantation. Proc (Bayl Univ Med Cent) 2012; 25: 49–57.
2.
Cooper DK, Ezzelarab MB, Hara H, Iwase H, Lee W, Wijkstrom M, et al: The pathobiology of pig-to-primate xenotransplantation: a historical review. Xenotransplantation 2016; 23: 83–105.
3.
Galili U, Mandrell RE, Hamadeh RM, Shohet SB, Griffiss JM: Interaction between human natural anti-alpha-galactosyl immunoglobulin G and bacteria of the human flora. Infect Immun 1988; 56: 1730–1737.
4.
Good AH, Cooper DK, Malcolm AJ, Ippolito RM, Koren E, Neethling FA, et al: Identification of carbohydrate structures that bind human antiporcine antibodies: implications for discordant xenografting in humans. Transplant Proc 1992; 24: 559–562.
5.
Phelps CJ, Koike C, Vaught TD, Boone J, Wells KD, Chen SH, et al: Production of alpha 1,3-galactosyltransferase-deficient pigs. Science 2003; 299: 411–414.
6.
Cooper DK, Ekser B, Ramsoondar J, Phelps C, Ayares D: The role of genetically engineered pigs in xenotransplantation research. J Pathol 2016; 238: 288–299.
7.
Cozzi E, White DJ: The generation of transgenic pigs as potential organ donors for humans. Nat Med 1995; 1: 964–966.
8.
Azimzadeh AM, Kelishadi SS, Ezzelarab MB, Singh AK, Stoddard T, Iwase H, et al: Early graft failure of GalTKO pig organs in baboons is reduced by expression of a human complement pathway-regulatory protein. Xenotransplantation 2015; 22: 310–316.
9.
Padler-Karavani V, Varki A: Potential impact of the non-human sialic acid N-glycolylneuraminic acid on transplant rejection risk. Xenotransplantation 2011; 18: 1–5.
10.
Byrne GW, Du Z, Stalboerger P, Kogelberg H, McGregor CG: Cloning and expression of porcine beta1,4 N-acetylgalactosaminyl transferase encoding a new xenoreactive antigen. Xenotransplantation 2014; 21: 543–554.
11.
Lutz AJ, Li P, Estrada JL, Sidner RA, Chihara RK, Downey SM, et al: Double knockout pigs deficient in N-glycolylneuraminic acid and galactose alpha-1,3-galactose reduce the humoral barrier to xenotransplantation. Xenotransplantation 2013; 20: 27–35.
12.
Estrada JL, Martens G, Li P, Adams A, Newell KA, Ford ML, et al: Evaluation of human and non-human primate antibody binding to pig cells lacking GGTA1/CMAH/β4GalNT2 genes. Xenotransplantation 2015; 22: 194–202.
13.
Buhler L, Awwad M, Basker M, Gojo S, Watts A, Treter S, et al: High-dose porcine hematopoietic cell transplantation combined with CD40 ligand blockade in baboons prevents an induced anti-pig humoral response. Transplantation 2000; 69: 2296–2304.
14.
Hara H, Witt W, Crossley T, Long C, Isse K, Fan L, et al: Human dominant-negative class II transactivator transgenic pigs – effect on the human anti-pig T-cell immune response and immune status. Immunology 2013; 140: 39–46.
15.
Reyes LM, Estrada JL, Wang ZY, Blosser RJ, Smith RF, Sidner RA, et al: Creating class I MHC-null pigs using guide RNA and the Cas9 endonuclease. J Immunol 2014; 193: 5751–5757.
16.
Buhler L, Basker M, Alwayn IP, Goepfert C, Kitamura H, Kawai T, et al: Coagulation and thrombotic disorders associated with pig organ and hematopoietic cell transplantation in nonhuman primates. Transplantation 2000; 70: 1323–1331.
17.
Cowan PJ, Robson SC, d’Apice AJ. Controlling coagulation dysregulation in xenotransplantation. Curr Opin Organ Transplant 2011; 16: 214–221.
18.
Mohiuddin MM, Singh AK, Corcoran PC, Thomas ML 3rd, Clark T, Lewis BG, et al: Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft. Nat Commun 2016; 7: 11138.
19.
Iwase H, Liu H, Wijkstrom M, Zhou H, Singh J, Hara H, et al: Pig kidney graft survival in a baboon for 136 days: longest life-supporting organ graft survival to date. Xenotransplantation 2015; 22: 302–309.
20.
Iwase H, Hara H, Ezzelarab M, Li T, Zhang Z, Gao B, et al: Immunological and physiological observations in baboons with life-supporting genetically engineered pig kidney grafts. Xenotransplantation 2017; 24.
21.
Ezzelarab MB, Ekser B, Azimzadeh A, Lin CC, Zhao Y, Rodriguez R, et al: Systemic inflammation in xenograft recipients precedes activation of coagulation. Xenotransplantation 2015; 22: 32–47.
22.
Higginbotham L, Mathews D, Breeden CA, Song M, Farris AB 3rd, Larsen CP, et al: Pre-transplant antibody screening and anti-CD154 costimulation blockade promote long-term xenograft survival in a pig-to-primate kidney transplant model. Xenotransplantation 2015; 22: 221–230.
23.
Higginbotham L, Kim S, Mathews D, Stephenson A, Breeden C, Larsen C, Ford M, Newell K, Tector A, Adams A: Late renal xenograft failure is antibody-mediated: description of the longest-reported survival in pig-to-primate renal xenotransplantation. Am Transplant Congress 2016;Abstract #A6.
24.
Shah JA, Patel MS, Elias N, Navarro-Alvarez N, Rosales I, Wilkinson RA, et al: Prolonged survival following pig-to-primate liver xenotransplantation utilizing exogenous coagulation factors and costimulation blockade. Am J Transplant 2017; 17: 2178–2185.
25.
Laird C, Burdorf L, Pierson RN 3rd: Lung xenotransplantation: a review. Curr Opin Organ Transplant 2016; 21: 272–278.
26.
Cooper DKC, Wijkstrom M, Hariharan S, Chan JL, Singh A, Horvath K, et al: Selection of patients for initial clinical trials of solid organ xenotransplantation. Transplantation 2017; 101: 1551–1558.
27.
Onions D, Cooper DK, Alexander TJ, Brown C, Claassen E, Foweraker JE, et al: An approach to the control of disease transmission in pig-to-human xenotransplantation. Xenotransplantation 2000; 7: 143–155.
28.
Tanabe T, Watanabe H, Shah JA, Sahara H, Shimizu A, Nomura S, et al: Role of intrinsic (graft) versus extrinsic (host) factors in the growth of transplanted organs following allogeneic and xenogeneic transplantation. Am J Transplant 2017; 17: 1778–1790.
29.
Cooper DKC, Pierson RN 3rd, Hering BJ, Mohiuddin MM, Fishman JA, Denner J, et al: Regulation of clinical xenotransplantation-time for a reappraisal. Transplantation 2017; 101: 1766–1769.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.