Xenotransplantation: Recent progress and current perspectives

Current Opinion in Immunology

Volumn 8, Issue 5, 1996, Pages 721-728

  Platt, Jeffrey L ^a  

^a DUKE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BLOOD VESSEL; CELLULAR IMMUNITY; HUMAN; IMMUNITY; NATURAL KILLER CELL; NONHUMAN; REVIEW; XENOGRAFT; XENOTRANSPLANTATION;

EID: 0030271853     PISSN: 09527915     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0952-7915(96)80091-4     Document Type: Article

References (69)

1. of special interest Platt JL. Hyperacute Xenograft Rejection. 1995;RG Landes Company, Austin, Texas, This book provides a comprehensive review of the clinical and pathological aspects of hyperacute xenograft rejection and considers how the pathogenesis of hyperacute rejection differs from the pathogenesis of other types of xenograft rejection.
2. Cooper DKC, Kemp E, Platt JL, White DJG. 2 Xenotransplantation; the Xenotransplantation of Organs and Tissues between Species. 1991;Springer-Verlag, Berlin, Heidelberg, New York, London, Paris, Tokyo, Hong Kong Barcelona, Budapest.
3. Parker W, Saadi S, Lin SS, Holzknecht ZE, Bustos M, Platt JL. Transplantation of discordant xenografts: a challenge revisited. Immunol Today. 17:1996;373-378.
4. Sandrin MS, Vaughan HA, Dabkowski PL, McKenzie IFC. Anti-pig IgM antibodies in human serum react predominantly with Galα(1,3)Gal epitopes. Proc Natl Acad Sci USA. 90:1993;11391-11395.
5. Parker WR, Bruno D, Holzknecht ZE, Platt JL. Xenoreactive natural antibodies: isolation and initial characterization. J Immunol. 153:1994;3791-3803.
6. Galili U, Macher BA, Buehler J, Shohet SB. Human natural anti-α-galactosyl IgG: the specific recognition of α(1-3)-linked galactose residues. J Exp Med. 162:1985;573-582.
7. Galili U, Swanson K. Gene sequences suggest inactivation of α-1, 3-galactosyltransferase in catarrhines after the divergence of apes from monkeys. Proc Natl Acad Sci USA. 88:1991;7401-7404.
8. Galili U, Shohet SB, Kobrin E, Stults CLM, Macher BA. Man, apes, and old world monkeys differ from other mammals in the expression of α-galactosyl epitopes on nucleated cells. J Biol Chem. 263:1988;17755-17762.
9. Good AH, Cooper DKC, Malcolm AJ, Ippolito RM, Koren E, Neethling FA, Ye Y, Zuhdi N, Lamontagne LR. Identification of carbohydrate structures that bind human antiporcine antibodies: implications for discordant xenografting in humans. Transplant Proc. 24:1992;559-562.
10. Collins BH, Parker WR, Platt JL. Characterization of porcine endothelial cell determinants recognized by human natural antibodies. Xenotransplantation. 1:1994;36-46.
11. of outstanding interest Collins BH, Cotterell AH, McCurry KR, Alvarado CG, Magee JC, Parker WR, Platt JL. Hyperacute rejection of cardiac xenografts between primate species: evidence to support the significance of the α-Galactosyl determinant. J Immunol. 154:1995;5500-5510 The organs from New World monkeys transplanted into baboons undergo hyperacute rejection; the antibodies deposited in the rejected graft are mainly specific for Galα1-3Gal. Thse results are the first evidence that the expression of Galα1-3Gal by an organ donor and the presence of Galα1-3Gal antibodies in a recipient may be sufficient basis for hyperacute rejection.
12. of outstanding interest Sachs DH, Sablinski T. Tolerance across discordant xenogeneic barriers. Xenotransplantation. 2:1995;234-239 In addition to providing a timely review of the rationale and one potential approach to inducing tolerance in a discordant species combination, this paper describes some fo the first studies in which specific absorption of Galα1-3Gal antibodies was found to prevent hyperacute rejection to pig to primate xenografts. The work mentioned in the paper thus supports the pre-eminent importance of Galα1-3Gal as a target of xenoreactive antibodies.
13. Platt JL, Fishel RJ, Matas AJ, Reif SA, Bolman RM, Bach FH. Immunopathology of hyperacute xenograft rejection in a swine-to-primate model. Transplantation. 52:1991;214-220.
14. of outstanding interest Magee JC, Collins BH, Harland RC, Lindman BJ, Bollinger RR, Frank MM, Platt JL. Immunoglobulin prevents complement mediated hyperacute rejection in swine-to-primate xenotransplantation. J Clin Invest. 96:1995;2404-2412 Administration of gamma globulin is shown to prevent hyperacute rejection of porcine organs by primates. The results demonstrate that in addition to activating the complement system, IgG can regulate activation of the complement system. The paper also provides evidence the xenoreactive natural IgG antibodies are probably not responsible for inducing rejection.
15. Platt JL, Vercellotti GM, Lindman BJ, Oegema TR Jr, Bach FH, Dalmasso AP. Release of heparan sulfate from endothelial cells: implications for pathogenesis of hyperacute rejection. J Exp Med. 171:1990;1363-1368.
16. of special interest Parker W, Lateef J, Everett ML, Platt JL. Specificity of xenoreactive anti-galα1-3gal IgM for α-galactosyl ligands. Glycobiology. 1996; Xenoreactive natural IgM antibodies bind in a homegeneous manner to Galα1-3Gal and yet a significant fraction of these antibodies do not recognize Galα1-6Glc or other α-galactosyl sugars, that had been commonly used for isolation and characterization of the antibodies. These results provide insight into the antibody-antigen interaction which may be useful in developing strategies fo immunoabsorption.
17. Ye Y, Neethling FA, Niekrasz M, Koren E, Richards SV, Martin M, Kosanke S, Oriol R, Cooper DKC. Evidence that intravenously administered α-Galactosyl carbohydrates reduce baboon serum cytotoxicity to pig kidney cells (PK15) and transplanted pig hearts. Transplantation. 58:1994;330-337.
18. of special interest Kooyman DL, Parker WR, McClellan SB, Avissar PL, Velardo MA, Platt JL, Logan JS. Identification and characterization of a galactosyl peptide mimetic. Transplantation. 61:1996;851-855 The authors use a peptide library to identify peptide sequences that adhere to and block xenoreactive IgM. This approach might be used to develop immunoabsorbants.
19. of outstanding interest Tearle RG, Tange MJ, Zannettino ZL, Katerelos M, Shinkel TA, Van Denderen BJW, Lonie AJ, Lyons I, Nottle MB, Cox T, et al. The α1,3-galactosyltransferase knockout mouse. Transplantation. 61:1996;13-19 The targeting of α1,3-galactosyltransferase reported in this paper provides important insights into the biology of the antibody-antigen system. First, the work demnstrates that expression of the enzyme is not necessary for life. Second, the paper shows that elimination of enzyme activity lead to a reduction by approximately 60% of the binding of human antibodies to the mutant cells. While the residual binding of antibodies may be a reason for concern, there is evidence from other laboratories that residual binding reflects in part the synthesis of neo-epitopes. Further, the authors point out in this review (see also [5,10,21,22]) that elimination of Galα1-3Gal from porcine cells by other means abolished antibody and complement activation.
20. of special interest Alvarado CG, Cotterell AH, McCurry KR, Collins BH, Magee JC, Berthold J, Logan JS, Platt JL. Variation in the level of xenoantigen expression in porcine organs. Transplantation. 59:1995;1589-1596 While it is now widely accepted that expression of Galα1-3Gal is necessary for the binding of xenoreactive antibodies to a porcine cell, studies documented in this paper suggest that it is not sufficient. Alvarado found that a seven-fold range in the binding of human Galα1-3Gal antibodies to cells from a large population of pigs was not related to differences in cell surface Galα1-3Gal. These observation are consistent with the concept that the binding of xenoreactive antibodies to a cell surface is influenced to a large extent by the three-dimensional array of epitopes which depends in turn on the nature of the protein core and its positioning on the cell surface.
21. of outstanding interest Sandrin MS, Fodor WL, Mouhtouris E, Osman N, Cohney S, Rollins SA, Guilmette ER, Setter E, Squinto SP, McKenzie I. Enzymatic remodelling of the carbohydrate surface of a xenogeneic cell substantially reduces human antibody binding and complement-mediated cytolysis. Nat Med. 1:1995;1261-1267 This paper reports that expression of H transferase (α1,2-fucosyltransferase) by cells which ordinarily synthesize Galα1-3Gal diverts synthesis of oligosaccharide termini away from Galα1-3Gal in favor of H antigen. The observation offers what may be an important avenue for the genetic engineering of donor animals for xenotransplantation (indeed, [22] reports the production of transgenic pigs using this strategy). This paper may also provide a system for analysis of how glycosyltransferases are utilized selectively in the Golgi apparatus to generate functionally important oligosaccharide sequences.
22. of outstanding interest Sharma A, Okabe JF, Birch P, Platt JL, Logan JS. Reduction in the level of gal (α1,3) gal in transgenic mice and pigs by the expression of an α(1,2) fucosyltransferase. Proc Natl Acad Sci USA. 93:1996;7190-7195 The authors report the development of transgenic pigs expressing H transferase. Synthesis of Galα1-3Gal in the transgenic pigs is notably diminished. This paper demonstrates how genetic engineering can potentially be used to address the molecular hurdles to xenotransplantation.
23. Leventhal JR, Matal AJ, Sun LH, Reif S, Bolman RM III, Dalmasso AP, Platt JL. The immunopathology of cardiac xenograft rejection in the guinea pig to rat model. Transplantation. 56:1993;1-8.
24. Leventhal JR, Dalmasso AP, Cromwell JW, Platt JL, Manivel CJ, Bolman RM, Matas AJ. Prolongation of cardiac xenograft survival by depletion of complement. Transplantation. 55:1993;857-866.
25. Pruitt SK, Kirk AD, Bollinger RR, Marsh HC Jr, Collins BH, Levin JL, Mault JR, Heinle JS, Ibrahim S, Rudolph AR, et al. The effect of soluble complement receptor type 1 on hyperacute rejection of porcine xenografts. Transplantation. 57:1994;363-370.
26. Brauer RB, Baldwin WM III, Daha MR, Pruitt SK, Sanfilippo F. Use of C6-deficient rats to evaluate the mechanism of hyperacute rejection of discordant cardiac xenografts. J Immunol. 151:1993;7240-7248.
27. Platt JL, Vercellotti GM, Dalmasso AP, Matas AJ, Bolman RM, Najarian JS, Bach FH. Transplantation of discordant xenografts: a review of progress. Immunol Today. 11:1990;450-456.
28. Dalmasso AP, Vercellotti GM, Platt JL, Bach FH. Inhibition of complement-mediated endothelial cell cytotoxicity by decay accelerating factor: potential for prevention of xenograft hyperacute rejection. Transplantation. 52:1991;530-533.
29. of outstanding interest McCurry KR, Kooyman DL, Alvarado CG, Cotterell AH, Martin MJ, Logan JS, Platt JL. Human complement regulatory proteins protect swine-to-primate cardiac xenografts from humoral injury. Nat Med. 1:1995;423-427 This paper reported the first use to transgenic pigs as xenograft donors. The expression of human CD59 and decay accelerating factor in porcine organs conferred significant protection agains complement-mediated injury and thus demonstrated the intrinsic susceptibility of an organ to heterologous complement is an important barrier to xenotransplantation.
30. of outstanding interest Thompson C. Humanised pigs hearts boost xenotransplantation. Lancet. 346:1995;766 This news item reports experiments soon to be reported (White, personal communication), that demonstrated extended survival of cardiac xenografts expressing human decay accelerating factor. While a formal report of the experiments is pending, the results would seem to offer encouragement that there may not be overwhelming nonimmunological hurdles to transplanting porcine organs into primates. For a description of the pigs used in these experiments the reader is referred to [31].
31. Rosengard BR, Adachi H, Ueda K, Hall TS, Hutchins GM, Herskowitz A, Borkon AM, Baumgartner WA, Reitz BA. Differences in the pathogenesis of first-set allograft rejection and acute xenograft rejection as determined by sequential morphologic analysis. J Heart Transpl. 5:1986;263-266.
32. of special interest Brauer R, Baldwin WM, Ibrahim S, Sanfilippo F. The contribution of terminal complement components to acute the hyperacute allograft rejection in the rat. Transplantation. 59:1995;288-293 This paper adds to evidence previously reported by these authors that the terminal complement complexes are necessary to the generating of hyper-acute rejection. This information is important for analyzing how complement mediates tissue injury not only in rejection but also in other immune-mediated diseases. See also annotations for [34,35] for consideration in a porcine to primate system, the reader is referred to [33].
33. of outstanding interest Kroshus TJ, Rollins SA, Dalmasso AP, Elliott EA, Matil LA, Squinto SP, Bolman RM. Complement inhibition with an anti-C5 monocional antibody prevents acute cardiac tissue injury in an ex vivo model of pig-to-human xenotransplantation. Transplantation. 60:1995;1194-1202.
34. of outstanding interest Diamond LE, McCurry KR, Oldham ER, McClellan SB, Martin MJ, Platt JL, Logan JS. Characterization of transgenic pigs expressing functionally active human CD59 on cardiac endothelium. Transplantation. 61:1996;1241-1249 Organs from pigs transgenic for CD59 are partially protected from injury but are hyperacutely rejected by baboons even though the amount of membrane attack complex antigen in the organs is notably less than in controls. These results suggest that the development of hyperacute rejection may not depend absolutely on the assembly of the membrane attack complex. How this result can be reconciled with the results reported in [32] is suggested in [35].
35. of special interest Saadi S, Platt JL. Transient perturbation of endothelial integrity induced by antibodies and complement. J Exp Med. 181:1995;21-31 The activation of complement on endothelial cells disrupts the integrity of the endothelial cell monolayer. The findings in this paper may help to explain how complement may mediate hyperacute rejection. Since the changes are induced by C5b67 complexes, the findings may explain why hyperacute rejection can occur under conditions in which assembly of the membrane attack complex is inhibited.
36. of outstanding interest Ihrcke NS, Wrenshall LE, Lindman BJ, Platt JL. Role of heparan sulfate in immune system-blood vessel interactions. Immunol Today. 14:1993;500-505.
37. of outstanding interest Ihrcke NS, Platt JL. Shedding of heparan sulfate proteoglycan by stimulated entodhelial cells: evidence for proteolysis of cell surface molecules. J Cell Physiol. 1996; The biochemical mechanism underlying complement-mediated release of heparan sulfate from endothelial cells is described. This change in endothelial cell metabolism may account in part of alterations in endothelial integrity and in coagulant and inflammatory properties of endothelium that are observed in xenografts undergoing rejection.
38. Satake M, Kawagishi N, Rydberg L, Samuelsson BE, Tibell A, Groth C, Moller E. Limited specificity of xenoantibodies in diabetic patients transplanted with fetal porcine islet cell clusters. Main antibody reactivity against α-linked galactose-containing epitopes. Xenotransplantation. 1:1994;89-101.
39. of outstanding interest Cotterell AH, Collins BH, Parker W, Harland RC, Platt JL. The humoral immune response in humans following cross-perfusion of porcine organs. Transplantation. 60:1995;861-868 Patients exposed briefly to porcine organ synthesize increased amounts of Galα1-3Gal antibodies. The kinetics of the antibody response and the specificity of the antibodies may contribute to unerstanding the pathogenesis of acute vascular xenograft rejection.
40. Leventhal JR, Sakiyalak P, Witson J, Simone P, Matas AJ, Bolman RM, Dalmasso AP. The synergistic effect of combined antibody and complement depletion on discordant cardiac xenograft survival in nonhuman primates. Transplantation. 57:1994;974-978.
41. of outstanding interest Saadi S, Holzkhecht RA, Patte CP, Stern DM, Platt JL. Complement-mediated regulation of tissue factor activity in endothelium. J Exp Med. 182:1995;1807-1814 This paper reports that complement causes the 'activation' of endothelial cells via a novel pathway in which IL-1α, the synthesis of which is induced by small amount of the membrane attack complex, acts as an autocrine factor to induce de novo sysnthesis fo tissue factors. The findings may help to explain the pathogenesis of acute vascular xenograft rejection.
42. of special interest Holzknecht Ze, Platt JL. Identification of porcine endothelial cell membrane antigens recognized by human xenoreactive antibodies. J Immunol. 154:1995;4565-4575 Human xenoreactive antibodies recognize Galα1-3Gal as a substitution on porcine endothelial cell membrane integrins. Perturbation of endothelial cell integrins or von Willebrand factor, to which the antibodies also bind, may help to explain the pathogenesis of acute vascular xenograft rejection. See also [43].
43. of outstanding interest Vaughan HA, McKenzie IFC, Sandrin MS. Biochemical studies of pig xenoantigens detected by naturally occurring human antibodies and the galactoseα(1-3)galactose reactive lectin. Transplantation. 59:1995;102-109 This paper, along with [42], describes porcine glycoproteins which by expression of Galα1-3Gal may serve as antigenic targets for xenoreactive natural antibodies.
44. of outstanding interest Inverardi L, Samaja M, Motterlini R, Mangili F, Bender JR, Pardi R. Early recognition of a discordant xenogeneic organ by human circulating lymphocytes. J Immunol. 149:1992;1416-1423. of special interest.
45. Blakely ML, Van Der Werf WJ, Berndt MC, Dalmasso AP, BAch FH, Hancock WW. Activation of intragraft endothelial and mononuclear cells during discordant xenograft rejection. Transplantation. 58:1994;1059-1066.
46. Zehr KJ, Herskowitz A, Lee PC, Kumar P, Gillinov AM, Baumgartner WA. Neutrophil adhesion and complement inhibition prolongs survival of cardiac xenografts in discordant species. Transplantation. 57:1994;900-906.
47. Hancock WW, Blakely ML, Van Der Werf W, Bach FH. Rejection of guinea pig cardiac xenografts post-cobra venom factor therapy is associated with infiltration by mononuclear cells secreting interferon-gamma and diffuse endothelial activation. Transplant Proc. 25:1993;2932.
48. of outstanding interest Malyguine AM, Platt JL, Saadi S, Dawson JR. Human natural killer cells induce morphologic changes in porcine endothelial cell monolayers. Transplantation. 51:1996;161-164 NK cells pertub the integrity of an endothelial cell monolayer. This observation offers one potential mechanism by which NK cells could induce xenograft injury.
49. of outstanding interest Goodman DJ, Albertini MV, Willson A, Millan MT, Bach FM. Direct activation of porcine endothelial cells by human natural killer cells. Transplantation. 61:1996;763-771 The pathogenesis of acute vascular xenograft rejection is often linked to endothelial cell activation and rejecting organs are someone found to contain NK cells (see also [47,48). This paper suggests that these observations may be related, since the activation of endothelial cells by NK cells might explain the development of rejection. This paper also underscores the importance of considering the noncytolytic effects of NK cells.
50. of outstanding interest Leventhal JR, John R, Fryer JP, Witson JC, Derlich J, Remiszewski J, Dalmasso A, Matas A, Bolman R. Removal of baboon and human antiporcine IgG and IgM natural antibodies by immunoadsorption: results of in vitro and in vivo studies. Transplantation. 59:1995;294-300 The authors of this report have used column technology to deplete immunoglobulins from xenograft recipients. The results offer insight into the role of immunoglobulins in xenograft rejection.
51. Lawson JH, Platt JL. Molecular barriers to xenotransplantation. Transplantation. 1996;. in press.
52. of outstanding interest Lawson JH, Daniels L, Platt JL. The evaluation of thrombomodulin activity in porcine to human xenotransplantation. Transplant Proc. 1996; Porcine thrombomodulin does not contribute effectively to the generation of human activated protein C. This incompatibility may help explain the profound susceptibility of xenograft to thrombosis. The authors also report a novel approach to the analysis of coagulation.
53. Auchincloss H Jr, Moses R, Conti D, Sundt T, Smith C, Sachs DH, Winn HJ. Rejection of transgenic skin expressing a xeno-class-I antigen is CD4-dependent and CD8-independent. Transplant Proc. 22:1990;1059-1060.
54. of outstanding interest Marchetti P, Scharp DW, Finke EH, Swanson CJ, Olack BJ, Gerasimidi-Vazeou D, Giannarelli R, Navaleski R, Lacy PE. Prolonged survival of discordant porcine islet xenografts. Transplantation. 61:1996;1100-1102 Treatment of mice with CD4 antibodies allows extended survival of porcine islet xenografts. This report adds to a growing body of evidence (see also [53]) including original studies from this laboratory [55] that some free tissue grafts can survive and function in phylogenetically-disparate recipients.
55. Ricordi C, Lacy PE, Sterbenz K, Davie JM. Low-temperature culture of human islets or in vivo treatment with L3T4 antibody produces a marked prolongation of islet human-to-mouse xenograft survival. Proc Natl Acad Sci USA. 84:1987;8080-8084.
56. Murray AG, Khodadoust MM, Pober JS, Bothwell ALM. Porcine aortic endothelial cells activate human T cells: direct presentation of MHC antigens and costimulation by ligands for human CD2 and CD28. Immunity. 1:1994;57-63.
57. Rollins SA, Kennedy SP, Chodera AJ, Elliott EA, Zavoico GB, Matis LA. Evidence that activation of human T cells by porcine endothelium involves direct recognition of porcine SLA and costimulation by porcine ligands for LFA-1 and CD2. Transplantation. 57:1994;1709-1716.
58. of outstanding interest Yamada K, Sachs DH, DerSimonian H. Human anti-porcine xenogeneic T cell response. Evidence for allelic specificity of mixed leukocyte reaction and for both direct and indirect pathways of recognition. J Immunol. 155:1995;5249-5256 Not only does the human T cell repertoire include T cells able to recognize porcine cells directly, see also [56], this paper reports studies demonstrating that proliferative responses are specific for pig MHC class II and exhibit the ability to distinguish one pig haplotype from another. The fine specificity of the T cell response will be come an important issue as xenotransplantation approaches the clinical arena and as the ability to select, breed or modify SLA expression may become an important avenue for limiting T cell responses.
59. + and subsequent costimulation.
60. Moses RD, Winn HJ, Auchincloss H Jr. Multiple defects in cell surface molecule interactions across species differences are responsible for diminished xenogeneic T cell responses. Transplantation. 53:1992;203-209.
61. of outstanding interest Wrenshall LE, Cerra FB, Singh RK, Platt JL. Heparan sulfate initiates signals in murine macrophages leading to divergent biological outcomes. J Immunol. 154:1995;871-880 Heparan sulfate, which can be released from endothelial cells by the action of complement, is shown to activate APCs through several signaling pathways. The action of heparan sulfate on APC could explain in part how humoral immune responses modulate cellular responses.
62. Chopek MW, Simmons RL, Platt JL. ABO incompatible renal transplantation: initial immunopathologic evaluation. Transplant Proc. 19:1987;4553-4557.
63. of special interest Yuzawa Y, Brett J, Fukatsu A, Matsuo S, Caldwell P, Niesen N, Milgrom F, Godman G, Stern D, Andres G. Interaction of antibody with forssman antigen in guinea pigs. Am J Pathol. 146:1995;1260-1272 The continuing interaction of antibody with blood vessels diminishes the effects of humoral immunity on the blood vessel. The diminished response is due in part to shedding of the target antigen on cell membrane vesicles and allows the animals to survive otherwise lethal injection of the antibody. These studies offer an elegant model for analysis of accommodation.
64. Sykes M, Lee LA, Sachs DH. Xenograft tolerance. Immunol Rev. 141:1994;245-276.
65. Li H, Ricordi C, Demetris AJ, Kaufman CL, Korbanic C, Hronakes ML, Ildstad ST. Mixed xenogeneic chimerism (mouse + rat mouse) to induce donor-specific tolerance to sequential or simultaneous islet xenografts. Transplantation. 57:1994;592-598.
66. Aksentijevich I, Sachs DH, Sykes M. Humoral tolerance in xenogeneic BMT recipients conditions by a nonmyeloablative regimen. Transplantation. 53:1992;1108-1114.
67. Gritsch HA, Glaser RM, Emery DW, Lee LA, Smith CV, Sablinski T, Arn JS, Sachs DH, Sykes M. The importance of nonimmune factors in reconstitution by discordant xenogenetic hematopoietic cells. Transplantation. 57:1994;906-917.
68. H families is consistent with the broad expression of the antibodies in the population and perhaps with structural constraints of antibody-protein interaction. The extent to which somatic mutation contributes to antibody function or is reflected by nominal changes in affinity of specificity, remains an important question. This paper offers the first direst investigation of the B cells which may be responsible for synthesizing Galα1-3Gal antibodies.
69. of outstanding interest Kooyman DL, Byrne GW, McClellan S, Nielsen D, Tone M, McCurry KR, Coffman TM, Waldmann H, Platt JL, Logan JS. in vivo transfer of GPI-linked complement restriction factors from erythrocytes to the endothelium. Sciences. 269:1995;89-92 An erythroid-specific promoter was used to express human complement regulatory proteins in transgenic mice. Surprisingly, the human protein was found in the endothelium in a functionally active form. This paper, along with [29], provides compelling evidence for spontaneous intercellular transfer of glycosyl phosphatidylinositol-linked proteins and suggests a novel approach for expressing a foreign protein on endothelial cells without gene transfer.