Therapeutic Strategies for Xenotransplantation

L. Bühler; M. R. Basker; I. P. J. Alwayn; D. H. Sachs; D. K. C. Cooper

doi:10.1128/9781555818043.ch6

Chapter 6 : Therapeutic Strategies for Xenotransplantation

Authors: L. Bühler¹, M. R. Basker¹, I. P. J. Alwayn¹, D. H. Sachs¹, D. K. C. Cooper¹

VIEW AFFILIATIONS HIDE AFFILIATIONS

Affiliations: 1: Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, MGH-East, Building 149-9019, 13th St., Boston, MA 02129

Content Type: Monograph

Publication Year: 2001

Category: Immunology

Book DOI: 10.1128/9781555818043

Chapter DOI: 10.1128/9781555818043.ch6

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:

Therapeutic Strategies for Xenotransplantation, Page 1 of 2

< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555818043/9781555811679_Chap06-1.gif /docserver/preview/fulltext/10.1128/9781555818043/9781555811679_Chap06-2.gif

Abstract:

To achieve successful xenotransplantation, it is necessary to overcome the immunological barriers that evolution has built up between different species. In contrast to allotransplantation, where the cellular response is the main hurdle, in xenotransplantation both humoral and cellular responses have to be overcome. In attempts to achieve successful pig-to-human xenotransplantation, several approaches are currently being evaluated. Genetic engineering techniques are being applied to the problems of xenotransplantation. To achieve successful xenotransplantation, it will probably be necessary to combine several therapeutic techniques and/or agents, as is the case with allotransplantation today. Xenotransplantation offers the first opportunity for modifying the donor as opposed to the recipient, which opens up new possibilities in this era of rapidly developing techniques such as genetic engineering, gene transfer, and cloning. The breeding of a pig with a vascular endothelial structure against which humans have no preformed antibodies would be a major advance. In the recipient, however, it will still be necessary to inhibit the production of induced antibodies, as well as the strong cellular response, either by some form of immunosuppressive therapy or by the induction of tolerance.

Citation: Bühler L, Basker M, Alwayn I, Sachs D, Cooper D. 2001. Therapeutic Strategies for Xenotransplantation, p 117-135. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch6

Key Concept Ranking

White Blood Cells: 0.6526515
Major Histocompatibility Complex: 0.60863066
B Cells: 0.5367442
Bone Marrow: 0.529734
Plasma Cell: 0.45129153

0.6526515

Highlighted Text: Show | Hide

Full text loading...

Figures

Therapeutic Strategies for Xenotransplantation

[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555818043.chap6-1,webId=/content/author/10.1128/9781555818043.chap6-1,properties={foaf_givenname=L., foaf_name=L. Bühler, foaf_surname=Bühler, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555818043.chap6-aff1]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555818043.chap6-2,webId=/content/author/10.1128/9781555818043.chap6-2,properties={foaf_givenname=M. R., foaf_name=M. R. Basker, foaf_surname=Basker, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555818043.chap6-aff1]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555818043.chap6-3,webId=/content/author/10.1128/9781555818043.chap6-3,properties={foaf_givenname=I. P. J., foaf_name=I. P. J. Alwayn, foaf_surname=Alwayn, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555818043.chap6-aff1]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555818043.chap6-4,webId=/content/author/10.1128/9781555818043.chap6-4,properties={foaf_givenname=D. H., foaf_name=D. H. Sachs, foaf_surname=Sachs, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555818043.chap6-aff1]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555818043.chap6-5,webId=/content/author/10.1128/9781555818043.chap6-5,properties={foaf_givenname=D. K. C., foaf_name=D. K. C. Cooper, foaf_surname=Cooper, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555818043.chap6-aff1]]}]]

/content/10.1128/9781555818043.chap6.fig6-1

Figure 1

Biosynthetic pathway for synthesis of Galαl-3Gal. The αl,3 galactosyltrans-ferase enzyme adds galactose to N-acetyllactosamine (Galβ1-4GlcNAc) to generate Galα1-3Gal. The same substrate can be utilized by transgenically introduced α1,2 fucosyltrans-ferase to produce the H histo-blood group epitope. Galαl-3Gal can also be eliminated by the introduction of α-galactosidase, which enables the N-acetyllactosamine substrate to be available again for further fucosylation. Modified from Sandrin et al. ( 70 ).

10.1128/9781555818043/fig6-1_thmb.gif

10.1128/9781555818043/fig6-1.gif

Figure 1

/content/10.1128/9781555818043.chap6.fig6-2

Figure 6

Anti-αGal IgG and IgM levels during treatment with anti-CD20 MAb (short arrows) and adsorption with EIA (long arrows). After four injections of anti-CD20 MAb and four of EIA, the level of anti-αGal IgM returned to pretreatment values within 2 weeks, whereas IgG remained below baseline.

10.1128/9781555818043/fig6-2_thmb.gif

10.1128/9781555818043/fig6-2.gif

Figure 6

/content/10.1128/9781555818043.chap6.fig6-3

Figure 3

Anti-αGal IgG and IgM responses following porcine peripheral blood mobilized progenitor cell (PBPC) transplantation in representative baboons receiving a tolerance-inducing regimen without (a) and with (b) anti-CD40L MAb. The arrows indicate the first day of porcine PBPC transplantation, which was administered after the extracorporeal immunoadsorption of anti-αGal antibodies, (a) A rise in both anti-αGal IgG and IgM occurred by day 10, indicating sensitization to the Gal determinants on the PBPC. (b) No rise in αGal-reactive IgG or IgM occurred, indicating that sensitization to Gal did not develop when anti-CD40L MAb was administered. The non-αGal-reactive anti-pig antibody response is shown expressed as median fluorescence intensity (MFI), in the same representative baboons treated without (c) and with (d) anti-CD40L MAb. The first column represents the total anti-pig antibody level, column 2 represents the same serum after immunoadsorption of anti-αGal antibody over an αGal matrix, and column 3 represents this serum after further depletion over a pig cell matrix. The difference between columns 1 and 2 therefore indicates the amount of anti-αGal antibody, and the difference between columns 2 and 3 indicates the amount of non-αGal anti-pig antibody, (c) Antibody directed to porcine non-αGal determinants on the PBPC developed within 20 days, (d) No antibody against porcine non-αGal determinants developed.

10.1128/9781555818043/fig6-3_thmb.gif

10.1128/9781555818043/fig6-3.gif

Figure 3

/content/10.1128/9781555818043.chap6.fig6-4

Figure 4

Detection by flow cytometry of pig cell chimerism in the blood of a baboon pretreated with a nonmyeloablative regimen and anti-CD40L MAb. The pig cells were injected on days 0 to 2, with detection of pig cells constituting up to 16% of the white blood cells in the baboon. These cells stained positive for a pig marker (pan pig) and for pig CD9 and pig MAC (monocyte and granulocyte markers). After day 5, no pig cells were detectable until day 16, when a pig monocyte population could be detected until day 22, indicating pig cell engraftment in the baboon.

10.1128/9781555818043/fig6-4_thmb.gif

10.1128/9781555818043/fig6-4.gif

Figure 4

References

/content/book/10.1128/9781555818043.chap6

1. Alexandre, G. P.,, J. R Squifflet,, M. De Bruyere,, D. Latinne,, R. Reding,, P. Gianello,, M. Carlier,, and Y. Pirson. 1987. Present experiences in a series of 26 ABO-incompatible living donor renal allografts. Transplant. Proc. 19: 4538– 4542.

2. Alexandre, G., R, R Gianello, and D. Latinne. 1989. Plasmapheresis and splenectomy in experimental renal xenotransplantation, p. 28. In M. A. Hardy (ed.), Xenograft 25. Elsevier, New York, N.Y.

3. Armitage, R. J.,, W. C. Fanslow,, L. Strockbine,, T. A. Sato,, K. N. Clifford,, B. M. Macduff,, D. M. Anderson,, S. D. Gimpel,, T. Davis-Smith,, C. R. Maliszewski,, E. A. Clark,, C. A. Smith,, K. H. Grabstein,, D. Cosman,, and M. K. Spriggs. 1992. Molecular and biological characterization of a murine ligand for CD40. Nature 357: 80– 82.

4. Azimzadeh, A.,, C. Meyer,, H. Watier,, J. P. Beller,, M. P. Chenard-Neu,, R. Kieny,, K. Boudjema,, D. Jaeck,, J. Cinqalbre,, and P. Wolf. 1998. Removal of primate xenoreactive natural antibodies by extracorporeal perfusion of pig kidneys and livers. Transplant. Immunol. 1: 13– 22.

5. Bach, F. H.,, H. Winkler,, C. Ferran,, W. W. Hancock,, and S. C. Robson. 1996. Delayed xenograft rejection. Immunol. Today 17: 379– 384.

6. Bracy, J. L.,, D. H. Sachs,, and J. Iacomini. 1998. Inhibition of xenoreactive natural antibody production by retroviral gene therapy. Science 281: 1845– 1847.

7. Biihler, L.,, M. Awwad,, M. Basker,, S. Gojo,, A. Watts,, S. Treter,, K. Nash,, G. Oravec,, Q. Chang,, A. Thall,, J. Down,, M. Sykes,, D. Andrews,, R. Sackstein,, M. White-Scharf,, D. H. Sachs,, and D. K. C. Cooper. 2000. High-dose porcine hematopoietic cell transplantation combined with CD40 ligand blockade in baboons prevents an induced anti-pig humoral response. Transplantation 69: 2296– 2304.

8. Chan, D. V.,, and H. Auchincloss, Jr. 1996. Human anti-pig cell-mediated cytotoxicity in vitro involves non-T as well as T cell components. Xenotransplantation 3: 158– 165.

9. Chrupcala, M.,, S. Pomer,, G. Staehler,, R. Waldherr,, and C. Kirschfink. 1994. Prolongation of discordant renal xenograft survival by depletion of complement. Comparative effects of systemically administered cobra venom factor and soluble complement receptor type 1 in a guinea pig to rat model. Transplant. Int. 7: S650.

10. Cooper, D. K. C. 1998. Xenoantigens and xenoantibodies. Xenotransplantation 5: 6– 17.

11. Cooper, D. K. C.,, T. D. H. Cairns,, and D. H. Taube. 1996. Extracorporeal immunoadsorption of anti-pig antibody in baboons using αGal oligosaccharide immunoaffinity columns. Xeno 4: 27– 29.

12. Cooper, D. K. C.,, P. A. Human,, G. Lexer,, A. G. Rose,, J. Rees,, M. Keraan,, and E. Dutoit. 1988. Effects of cyclosporine and antibody adsorption on pig cardiac xenograft survival in the baboon. J. Heart Lung Transplant. 7: 238– 246.

13. Cooper, D. K. C.,, E. Koren,, and R. Oriol. 1993. Genetically-engineered pigs. Lancet 342: 682– 683.

14. Cooper, D. K. C.,, E. Koren,, and R. Oriol. 1994. Oligosaccharides and discordant xenotransplantation. Immunol. Rev. 141: 31– 58.

15. Cooper, D. K. C.,, E. Koren,, and R. Oriol. 1996. Manipulation of the anti-αGal antibody-αGal epitope system in experimental discordant xenotransplantation. Xenotransplantation 3: 102– 111.

16. Cozzi, E.,, and D. J. G. White. 1995. The generation of transgenic pigs as potential organ donors for humans. Nature Med. 1: 964– 966.

17. Cozzi, E.,, N. Yannoutsos,, G. A. Langford,, G. Pino-Chavez,, J. Wallwork,, and D. J. G. White,. 1997. Effect of transgenic expression of human decay-accelerating factor on the inhibition of hyperacute rejection of pig organs, p. 665– 682. In D. K. C. Cooper,, E. Kemp,, J. L. Piatt,, and D. J. G. White (ed.), Xenotransplantation, 2nd ed. Springer, Heidelberg, Germany.

18. DeMarco, T.,, L. Damon,, B. Colombe,, F. Keigh,, K. Chatterjee,, and M. Garovoy. 1997. Successful immunomodulation with intravenous gamma globulin and cyclophosphamide in an alloimmunized heart transplant recipient. J. Heart Lung Transplant. 16: 360– 365.

19. Dwyer, J. M. 1987. Intravenous therapy with gamma globulin. Adv. Intern. Med. 32: 111– 135.

20. Dwyer, J. M. 1992. Manipulating the immune system with immune globulin. N. Engl. J. Med. 326: 107– 116.

21. Elwood, E. T.,, C. P. Larsen,, H. R. Cho,, M. Corbascio,, S. C. Ritchie,, D. Z. Alexander,, C. Tucker-Burden,, P. S. Linsley,, A. Aruffo,, D. Hollenbaugh,, K. J. Winn,, and T. C. Pearson. 1998. Prolonged acceptance of concordant and discordant xenografts with combined CD40 and CD28 pathway blockade. Transplantation 65: 1422– 1428.

22. Galili, U., 1997. Anti-agalactosyl (anti-Gal) damage beyond hyperacute rejection, p. 95– 103. In D. K. C. Cooper,, E. Kemp,, J. L. Platt,, and D. J. G. White (ed.), Xenotransplantation, 2nd ed. Springer, Heidelberg, Germany.

23. Galili, U.,, D. C. Latemple,, A. W. Walgenbach,, and K. R. Stone. 1997. Porcine and bovine cartilage transplants in cynomolgus monkeys: II. Changes in anti-gal response during chronic rejection. Transplantation 63: 646– 651.

24. Galili, U.,, S. B. Shohet,, E. Kobrin,, C. L. M. Stults,, and B. A. Macher. 1988. Man, apes and Old World monkeys differ from other mammals in the expression of αgalactosyl epitopes on nucleated cells. J. Biol. Chem. 263: 17755– 17762.

25. Gautreau, C.,, T. Kojima,, G. Woimant,, J. Cardoso,, P. H. Devillier,, and D. Houssin. 1995. Use of intravenous immunoglobulin to delay xenogeneic hyperacute rejection. An in vivo and in vitro evaluation. Transplantation 60: 903– 907.

26. Glotz, D.,, J. Haymann,, N. Sansonetti,, A. Francois,, V. Menoyo-Calonge,, J. Bariety,, and P. Druet. 1993. Suppression of HLA-specific alloantibodies by high-dose intravenous immunoglobulins (IVIG). Transplantation 56: 335– 337.

27. Good, A. H.,, D. K. C. Cooper,, A. J. Malcolm,, R. M. Ippolito,, E. Koren,, F. A. Neethling,, Y. Ye,, N. Zuhdi,, and L. R. Lamontagne. 1992. Identification of carbohydrate structures which bind human anti-porcine antibodies: implications for discordant xenografting in man. Transplant. Proc. 24: 559– 562.

28. Hansch, G.,, C. H. Hammer,, P. Vanguri,, and M. L. Shin. 1981. Homologous species restriction in lysis of erythrocytes by terminal complement proteins. Proc. Natl. Acad. Sci. USA 78: 5118– 5121.

29. Ierino, F. L.,, S. Gojo,, P. T. Bajerjee,, M. Giovino,, Y. Xu,, J. Gere,, C. Kaynor,, M. Awwad,, R. Monroy,, J. Rembert,, T. Hatch,, A. Foley,, T. Kozlowski,, K. Yamada,, F. A. Neethling,, J. Fishman,, M. Bailin,, R. R. Spitzer,, D. K. C. Cooper,, A. B. Cosimi,, C. LeGuern,, and D. H. Sachs. 1999. Transfer of swine major histocompatibility complex class II genes into autologous bone marrow cells of baboons for the induction of tolerance across xenogeneic barriers. Transplantation 67: 1119– 1128.

30. Ish, C.,, G. L. Ong,, N. Desai,, and M. J. Mattes. 1993. The specificity of alternative complement pathway-mediated lysis of erythrocytes: the survey of complement and target cells from 25 species. Scand. J. Immunol. 38: 113– 122.

31. Kaveri, S. V.,, G. Dietrich,, V. Hurez,, and M. D. Kazatchkine. 1991. Intravenous immunoglobulins (IVIG) in the treatment of autoimmune diseases. Clin. Exp. Immunol. 86: 192.

32. Kawai, T.,, A. B. Cosimi,, R. B. Colvin,, J. Powelson,, J. Eason,, T. Kozlowski,, M. Sykes,, R. Monroy,, M. Tanaka,, and D. S. Sachs. 1995. Mixed allogeneic chimerism and renal allograft tolerance in cynomolgus monkeys. Transplantation 59: 256– 262.

33. Kirk, A. D.,, L. C. Burkly,, D. S. Batty,, R. E. Baumgartner,, J. D. Berning,, K. Buchanan,, J. H. Fechner,, R. L. Germond,, R. L. Kampen,, N. B. Patterson,, S. J. Swanson,, D. K. Tadaki,, C. N. TenHor,, L. White,, S. J. Knechtle,, and D. M. Harlan. 1999. Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nature Med. 5: 686– 693.

34. Kirk, A. D.,, D. M. Harlan,, N. N. Armstrong,, T. A. Davis,, Y. Dong,, G. S. Gray,, X. Hong,, D. Thomas,, J. H. Fechner, Jr., and S. J. Knechtle. 1997. CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc. Natl. Acad. Sci. USA 94: 8789– 8794.

35. Kobayashi, T.,, E. Kemp,, and D. K. C. Cooper,. 1997. Prolongation of discordant xenograft survival by cobra venom factor, p. 425– 436. In D. K. C. Cooper,, E. Kemp,, J. L. Platt,, and D. J. G. White (ed.), Xenotransplantation, 2nd ed. Springer, Heidelberg, Germany.

36. Kobayashi, T.,, F. A. Neethling,, S. Taniguchi,, Y. Ye,, M. Niekrasz,, E. Koren,, W. W. Hancock,, H. Takagi,, and D. K. C. Cooper. 1996. Investigation of the anti-complement agents, FUT-175 and K76COOH, in discordant xenotransplantation. Xenotransplantation 3: 237– 245.

37. Kobayashi, T.,, S. Taniguchi,, F. A. Neethling,, A. G. Rose,, W. W. Hancock,, Y. Ye,, M. Niekrasz,, S. Kosanke,, L. J. Wright,, D. J. G. White,, and D. K. C. Cooper. 1997. Delayed xenograft rejection of pig-to-baboon cardiac transplants after cobra venom factor therapy. Transplantation 64: 1255– 1261.

38. Koren, E.,, F. Milotec,, F. A. Neethling,, M. Koscec,, D. Fei,, T. Kobayashi,, S. Taniguchi,, and D. K. C. Cooper. 1996. Monoclonal anti-idiotypic antibodies neutralize cytotoxic effects of anti-αGal antibodies. Transplantation 62: 837– 843.

39. Kozlowski, T.,, F. L. Ierino,, D. Lambrigts,, A. Foley,, D. Andrews,, M. Awwad,, R. Monroy,, A. B. Cosimi,, D. K. C. Cooper,, and D. H. Sachs. 1998. Depletion of anti-αGal l-3Gal antibody in baboons by specific immunoaffinity columns. Xenotransplantation 5: 122– 131.

40. Kozlowski, T.,, R. Monroy,, Y. Xu,, T. Glaser,, M. Awwad,, D. K. C. Cooper,, and D. H. Sachs. 1998. Anti-αGal antibody response to porcine bone marrow in unmodified baboons and baboons conditioned for tolerance induction. Transplantation 66: 176– 182.

41. Kozlowski, T.,, A. Shimizu,, D. Lambrigts,, K. Yamada,, Y. Fuchimoto,, R. Glaser,, R. Monroy,, Y. Xu,, M. Awwad,, R. B. Colvin,, A. B. Cosimi,, S. C. Robson,, J. Fishman,, T. R. Spitzer,, D. K. C Cooper,, and D. H. Sachs. 1999. Porcine kidney and heart transplantation in baboons undergoing a tolerance induction regimen and antibody adsorption. Transplantation 67: 18– 30.

42. Lambrigts, D.,, D. H. Sachs,, and D. K. C. Cooper. 1998. Discordant organ xenotransplantation in primates— world experience and current status. Transplantation 66: 547– 561.

43. Lambrigts, D.,, P. Van Calster,, X. Xu,, M. Awwad,, F. A. Neethling,, T. Kozlowski,, A. Foley,, A. Watts,, S. J. Chae,, J. Fishman,, A. D. Thall,, M. E. White-Scharf,, D. H. Sachs,, and D. K. C. Cooper. 1998. Pharmacologic immunosuppressive therapy and extracorporeal immunoadsorption in the suppression of anti-αGal antibody in the baboon. Xenotransplantation 5: 274– 283.

44. Larsen, C. P.,, E. T. Elwood,, D. Z. Alexander,, S. C. Ritchie,, R. Hendrix,, C. Tucker-Burden,, H. R. Cho,, A. Aruffo,, D. Hollenbaugh,, P. S. Linsley,, K. J. Winn,, and T. C. Pearson. 1996. Long-term acceptance of skin and cardiac allografts after blocking CD40 ligand. Nature 381: 434– 438.

45. Latinne, D.,, P. Gianello,, C. V. Smith,, V. Nickeleit,, T. Kawai,, M. Beadle,, C. Haug,, M. Sykes,, E. Lebowitz,, H. Bazin,, R. Colvin,, A. B. Cosimi,, and D. H. Sachs. 1993. Xenotransplantation from pig to cynomolgus monkey: an approach toward tolerance induction. Transplant. Proc. 250: 336– 338.

46. Leventhal, J. R.,, A. P. Dalmasso,, J. W. Cromwell,, J. L. Platt,, C. J. Manivel,, R. M. Bolman III,, and A. J. Matas. 1993. Prolongation of cardiac xenograft survival by depletion of complement. Transplantation 55: 857– 865.

47. Lexer, G.,, D. K. C. Cooper,, A. G. Rose,, W. N. Wicomb,, J. Rees,, M. Keraan,, and E. Du Toit. 1986. Hyperacute rejection in a discordant (pig-to-baboon) cardiac xenograft model. J. Heart Transplant. 5: 411– 418.

48. Lin, S. S.,, B. C. Weidner,, G. W. Byrne,, L. E. Diamond,, J. H. Lawson,, C. W. Hoopes,, L. J. Daniels,, C. W. Daggett,, W. Parker,, R. C. Harland,, R. D. Davis,, R. R. Bollinger,, J. S. Logan,, and J. L. Platt. 1998. The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants. J. Clin. Invest. 101: 1745– 1756.

49. Macchiarini, P.,, R. Oriol,, A. Azimzadeh,, V. De Montpreville,, R. Rieben,, N. Bovin,, M. Mazmanian,, and P. Dartevelle. 1998. Evidence of human non-alpha-galactosyl antibodies involved in the hyperacute rejection of pig lungs and their removal by pig organ perfusion. J. Thorac. Cardiovasc. Surg. 5: 831– 843.

50. Magee, J. C.,, B. H. Collins,, R. C. Harland,, B. J. Lindman,, R. R. Bollinger,, M. M. Frank,, and J. L. Platt. 1995. Immunoglobulin prevents complement-mediated hyperacute rejection in swine-to-primate xenotransplantation. J. Clin. Invest. 96: 2404– 2412.

51. Marsh, H. C.,, and U. S. Ryan,. 1997. The therapeutic effect of soluble complement receptor type I (sCRl) in xenotransplantation, p. 437– 455. In D. K. C. Cooper,, E. Kemp,, J. L. Platt,, and D. J. G. White (ed.), Xenotransplantation, 2nd ed. Springer, Heidelberg, Germany.

52. McCurry, K. R.,, D. L. Kooyman,, C. G. Alvarado,, A. H. Cotterell,, M. J. Martin,, J. S. Logan,, and J. L. Platt. 1995. Human complement regulatory proteins protect swine-to-primate cardiac xenografts from humoral injury. Nature Med. 1: 423– 427.

53. Mclntyre, J.,, N. Higgins,, R. Britton,, S. Faucett,, S. Johnson,, D. Beckman,, D. Hormuth,, J. Fehrenbacher,, and H. Halbrook. 1996. Utilization of intravenous immunoglobulin to ameliorate alloantibodies in a highly sensitized patient with a cardiac assist device awaiting heart transplantation. Transplantation 62: 691– 693.

54. Moberg, A. W.,, A. R. Shons,, H. Gerwurz,, M. Mozes,, and J. S. Najarian. 1971. Prolongation of renal xenografts by the simultaneous sequestration of preformed antibody, inhibition of complement, coagulation, and antibody synthesis. Transplant. Proc. 3: 538– 541.

55. Moses, R. D.,, and H. Auchincloss,. 1997. Mechanism of cellular xenograft rejection, p. 140– 174. In D. K. C. Cooper,, E. Kemp,, J. L. Platt,, and D. J. G. White (ed.), Xenotransplantation, 2nd ed. Springer, Heidelberg, Germany.

56. Murray, A. G.,, M. M. Khodadoust,, J. S. Pober,, and A. L. Rothwell. 1994. Porcine aortic endothelial cellsactivate human T cells: direct presentation of MHC antigens and costimulation by ligands for human CD2and CD28. Immunity 1: 57– 63.

57. Noelle, R.,, M. Roy,, D. Shepherd,, I. Stamenkovic,, J. Ledbetter,, and A. Aruffo. 1992. A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells. Proc. Natl. Acad. Sci. USA 89: 6550– 6554.

58. Oriol, R.,, Y. Ye,, E. Koren,, and D. K. C. Cooper. 1993. Carbohydrate antigens of pig tissues reacting with human natural antibodies as potential targets for hyperacute vascular rejection in pig-to-man organ xenotransplantation. Transplantation 56: 1433– 1442.

59. Ostlie, D. J.,, E. Cozzi,, C. M. Vial,, F. N. K. Bhatti,, G. Pino-Chavez,, S. Thiru,, B. Soin,, D. J. G. White,, and P. J. Friend. 1999. Improved renal function and fewer rejection episodes using SDZ RAD in life-supporting hDAF pig-to-primate renal xenotransplantation. Abstr. Am. Soc. Transplant..

60. Palmer, A.,, D. Taube,, K. Welsh,, M. Bewick,, P. Gjorstrup,, and M. Thick. 1989. Removal of HLA antibodies by extracorporeal immunoadsorption to enable renal transplantation. Lancet i: 10– 12.

61. Perper, R. J.,, and J. S. Najarian. 1966. Experimental renal heterotransplantation. I. In widely divergent species. Transplantation 4: 377– 388.

62. Pretagostini, R.,, P. Berloco,, L. Poli,, P. Cinti,, A. Di Nicuolo,, P. De Simone,, M. Colonnello,, A. Salerno,, D. Alfani,, and R. Cortesini. 1996. Immunoadsorption with protein A in humoral rejection of kidney trans-plants. ASAIO Journal 42: M645– M648.

63. Pruitt, S. K.,, W. M. Baldwin,, H. C. Marsh, Jr.,, S. S. Lin,, C. G. Yeh,, and R. R. Bollinger. 1991. The effect of soluble complement receptor type 1 on hyperacute xenograft rejection. Transplantation 52: 868– 873.

64. Pruitt, S. K.,, A. D. Kirk,, R. R. Bollinger,, H. C. Marsh, Jr.,, B. H. Collins,, J. L. Levin,, J. R. Mault,, J. S. Heinle,, S. Ibrahim,, and A. R. Rudolph. 1994. The effect of soluble complement receptor type 1 on hyperacute rejection of porcine xenografts. Transplantation 57: 363– 370.

65. Reed, E.,, M. Hardy,, A. Benvenisty,, C. Lattes,, J. Brensilver,, R. McCabe,, K. Reemstma,, D. W. King,, and N. Suciu-Foca. 1987. Effect of antiidiotypic antibody to HLA on graft survival in renal allograft recipients. N. Engl. J. Med. 316: 1450– 1455.

66. Romano, E.,, F. A. Neethling,, K. Nilsson,, S. Kosanke,, A. Shimizu,, S. Magnusson,, L. Svensson,, B. Samuelsson,, and D. K. C. Cooper. 1999. Intravenous synthetic αGal saccharides delay hyperacute rejection of a pig-to-baboon heart transplant. Xenotransplantation 6: 36– 42.

67. Rossi, F.,, G. Dietrich,, and M. D. Kazatchkine. 1989. Antiidiotypic suppression of autoantibodies with normal polyspecific immunoglobulins. Res. Immunol. 140: 19– 31.

68. Sablinski, T.,, D. Latinne,, P. Gianello,, M. Bailin,, K. Bergen,, R. B. Colvin,, A. Foley,, H. Z. Hong,, S. Meehan,, R. Monroy,, J. A. Powelson,, M. Sykes,, M. Tanaka,, A. B. Cosimi,, and D. H. Sachs. 1995. Xenotransplantation of pig kidneys to nonhuman primates: I. Development of the model. Xenotransplantation 2: 264– 270.

69. Sachs, S. H.,, G. Leight,, J. Cone,, S. Schwarz,, L. Stuart,, and S. Rosenberg. 1976. Transplantation in miniature swine. I. Fixation of the major histocompatibility complex. Transplantation 22: 559– 567.

70. Sandrin, M. S.,, S. Cohney,, N. Osman,, and I. F. C. McKenzie,. 1997. Overcoming the anti-Galαl-3Gal reaction to avoid hyperacute rejection: molecular genetic approaches, p. 683– 700. In D. K. C. Cooper,, E. Kemp,, J. L. Platt,, and D. J. G. White (ed.), Xenotransplantation, 2nd ed. Springer, Heidelberg, Germany.

71. Sandrin, M. S.,, W. L. Fodor,, E. Mouhtouris,, N. Osman,, S. Cohney,, S. A. Rollins,, E. R. Guilmette,, E. Setter,, S. P. Squinto,, and I. F. C. McKenzie. 1995. Enzymatic remodeling of the carbohydrate surface ofa xenogenic cell substantially reduces human antibody binding and complement-mediated cytolysis. NatureMed. 1: 1261– 1267.

72. Schmoeckel, M.,, F. N. K. Bhatti,, A. Zaidi,, E. Cozzi,, P. D. Waterworth,, M. J. Tolan,, M. Goddard,, R. G. Warner,, G. A. Langford,, J. J. Dunning,, J. Wallwork,, and D. J. G. White. 1998. Orthotopic heart transplantation in a transgenic pig-to-primate model. Transplantation 65: 1570– 1577.

73. Sharabi, Y.,, V. S. Abraham,, M. Sykes,, and D. H. Sachs. 1992. Mixed allogeneic chimeras prepared by a non-myeloablative regimen: requirement for chimerism to maintain tolerance. Bone Marrow Transplant. 9: 191– 197.

74. Sharabi, Y.,, I. Aksentijevich,, T. M. Sundt IH,, D. H. Sachs,, and M. Sykes. 1990. Specific tolerance induction across a xenogeneic barrier: production of mixed rat/mouse lymphohematopoietic chimeras using a nonlethal preparative regimen. J. Exp. Med. 172: 195– 202.

75. Shorts, A. R.,, M. Beir,, J. Jetzer,, and J. S. Najarian. 1973. Techniques of in vivo plasma modification for the treatment of hyperacute rejection. Surgery 73: 28– 37.

76. Simon, P.,, F. A. Neethling,, S. Taniguchi,, P. L. Good,, D. Zopf,, W. W. Hancock,, and D. K. C. Cooper. 1998. Intravenous infusion of αGal oligosaccharides in baboons delays hyperacute rejection of porcine heart xenografts. Transplantation 65: 346– 353.

77. Slapak, M.,, M. Greenbaum,, W. Bardawil,, C. Saravis,, J. Joison,, and W. V. McDermott, Jr. 1971. Effect of heparin, arvin, liver perfusion, and heterologous antiplatelet serum on rejection of pig kidney to dog. Transplant. Proc. 3: 558– 561.

78. Taniguchi, S.,, F. A. Neethling,, E. Y. Korchagina,, N. Bovin,, Y. Ye,, T. Kobayashi,, M. Niekrasz,, S. Li,, E. Koren,, R. Oriol,, and D. K. C. Cooper. 1996. In vivo immunoadsorption of antipig antibodies in baboons using a specific Galαl-3Gal column. Transplantation 10: 1379– 1384.

79. Terman, D. S.,, R. Garcia-Rinaldi,, R. McCalmon,, C. C. Crumb,, C. Mattioli,, G. Cook,, and R. Poser. 1979. Modification of hyperacute renal xenograft rejection after extracorporeal immunoadsorption of heterospecific antibody. Int. J. Artif. Organs 2: 35– 41.

80. Tyan, D.,, V. A. Li,, L. Czer,, A. Trento,, and S. Jordan. 1994. Intravenous immunoglobulin suppression of HLA alloantibody in highly sensitized transplant candidates and transplantation with a histoincompatible organ. Transplantation 57: 553– 562.

81. Vial, C. M.,, D. H. Ostlie,, E. Cozzi,, G. Pino-Chavez,, S. Thiru,, D. J. G. White,, and P. J. Friend. 1999. Mycophenolic acid-sodium (ERL080) permits prolonged function in hDAF pig-to-primate renal xenotransplantation. Abstr. Am. Soc. Transplant Surgeons.

82. Weisman, H. F.,, T. Bartow,, M. K. Leppo,, H. C. Marsh, Jr.,, G. R. Carson,, M. F. Concino,, M. P. Boyle,, K. H. Roux,, M. L. Weisfeldt,, and D. T. Fearon. 1990. Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis. Science 249: 146– 151.

83. Wekerle, T.,, M. H. Sayegh,, J. Hill,, Y. Zhao,, A. Chandraker,, K. G. Swenson,, G. Zhao,, and M. Sykes. 1998. Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is followed by central T cell tolerance. J. Exp. Med. 187: 2037– 2044.

84. White, D. J. G.,, G. A. Langford,, E. Cozzi,, and V. J. Young. 1995. Production of pigs transgenic for human DAF. A strategy for xenotransplantation. Xenotransplantation 2: 213– 217.

85. Wilmut, I.,, A. E. Schnieke,, J. McWhir,, A. J. Kind,, and K. H. Campbell. 1997. Viable offspring derived from fetal and adult mammalian cells. Nature 385: 810– 813.

86. Xia, W.,, D. T. Fearon,, and R. L. Kirkman. 1993. Effect of repetitive doses of soluble human complement receptor type 1 on survival of discordant cardiac xenografts. Transplant. Proc. 25: 410– 411.

87. Xu, Y.,, T. Lorf,, T. Sablinski,, P. Gianello,, M. Bailin,, R. Monroy,, T. Kozlowski,, M. Awwad,, D. K. C. Cooper,, and D. H. Sachs. 1998. Removal of anti-porcine natural antibodies from human and nonhuman primate plasma in vitro and in vivo by a Galαd-3Gal βl-4Glc-X immunoaffinity column. Transplantation 65: 172– 179.

88. Yamada, K.,, D. H. Sachs,, and H. DerSimonian. 1995. The human anti-porcine xenogeneic T-cell response: evidence for allelic specificity of MLR and for both direct and indirect pathways of recognition. J. Immunol. 155: 5249– 5256.

89. Yamada, K.,, J. D. Seebach,, H. DerSimonian,, and D. H. Sachs. 1996. Human anti-pig T-cell mediated cytotoxicity. Xenotransplantation 3: 179– 187.

90. Yang, Y. G.,, E. DeGoma,, H. Ohdan,, J. L. Bracy,, Y. Xu,, J. Iacomini,, A. D. Thall,, and M. Sykes. 1998. Tolerization of anti-Gala l-3Gal natural antibody-forming B cells by induction of mixed chimerism. J. Exp. Med. 187: 1335– 1342.

91. Ye, Y.,, F. A. Neethling,. M. Niekrasz,, E. Koren,, S. V. Richards,, M. Martin,, S. Kosanke,, R. Oriol,, and D. K. C. Cooper. 1994. Evidence that intravenously administered alpha-galactosyl carbohydrates reduce baboon serum cytotoxicity to pig kidney cells (PK15) and transplanted pig hearts. Transplantation 58: 330– 337.

92. Zaidi, A.,, M. Schmoeckel,, F. N. K. Bhatti,, P. D. Watterworth,, M. J. Tolan,, E. Cozzi,, G. Chavez,, G. A. Langford,, S. Thiru,, J. Wallwork,, D. J. G. White,, and P. Friend. 1998. Life-supporting pig-to-primate renal xenotransplantation using genetically modified donors. Transplantation 65: 1584– 1590.