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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Theor Med Bioeth. Author manuscript; available in PMC 2010 November 29.
Published in final edited form as:
Theor Med Bioeth. 1998 September; 19(5): 441–455.
PMCID: PMC2993097
NIHMSID: NIHMS250019

TRANSPLANTATION TOLERANCE, MICROCHIMERISM, AND THE TWO-WAY PARADIGM

1. INTRODUCTION

Melvin Cohn has extolled the virtues of immunologic hypotheses which accommodate all relevant observations as opposed to concise “small theories” that explain only a few facts.1 Exemplifying Cohn’s argument, the inability to evolve an encompassing explanation for observations made in human and animal allograft recipients, or in surrogate in vitro models, has driven much of transplantation research down a reductionist pathway.

Two premises that were introduced into transplantation immunology between 1944 and 1959 explain why. One was that the events following transplantation could be defined in terms of one-way immune reactions: host versus graft (HVG) and graft versus host (GYH). When this assumption was combined with the second premise that whole organ allograft “acceptance” was fundamentally different from the chimerism-dependent acquired tolerance of Billingham, Brent, and Medawar2,3, a derivative dogma emerged that we have called “the one-way paradigm”.4

2. THE Y IN THE ROAD: 1962

Until 1959, the production of chimerism by donor leukocyte infusion in preparation for organ allotransplantation was a much anticipated natural extension5,6 of the neonatal tolerance models of Billingham, Brent, and Medawar2,3 and of the adult rodent analogues that required recipient cytoablation.7,8 In both the neonatal and cytoablation models, the transplanted leukocytes caused graft-versus-host disease (GVHO) unless there was close donor/recipient histocompatibility.9–11

When long survival of functioning human kidney allografts was accomplished in sublethally irradiated recipients (1959–1962) without donor leukocyte infusion 1214 and then regularly (1962 onward) using continuous pharmacologic immunosuppression and no cytoreduction, 15–16 the need in organ transplantation for both chimerism and recipient preconditioning seemingly had been eliminated. These conclusions also defocused an understanding of bone marrow transplantation which was widely construed to be an example of total donor leukocyte chimerism: i.e. complete replacement of the immune system.

Because there was little room for immune interactions (i.e. combined HVG and GVH responses) in the evolving framework of transplantation immunology, objections to the simplistic concept of a one-way reaction were not taken seriously. In their alternative hypothesis, Simonsen,19 supported by Michie, Woodruff, and Zeiss,20 postulated in 1960–1961 that coexisting donor and recipient immune cells in neonatally tolerant mice had achieved a mutually nonreactive state while retaining the ability to function collaboratively (e.g. in a joint immune response to infection). Interest in this hypothesis evaporated when Simonsen recanted it in 1962,21 largely because no experimental support could be found.

In addition, however, nothing less than host clonal deletion to explain acquired transplantation tolerance appeared to be compatible with the consensus of that time. The disputes about clonal selection as the basis for self/non-self delineation seemingly had been brought to closure by the ultimate imprimatur of the Nobel Prize, which was awarded to MacFarland Burnet in 1960.22,23 It was no coincidence that the 1960 co-laureate with Burnet was Peter Brian Medawar, whose observations in the neonatal tolerance model2,3 were widely considered to be a validation of Burnet’s prediction that developing lymphocytes with an open repertoire of receptors could be purged of self-reactive cells before they achieved functional maturity. The tolerance produced in radiation chimeras 7,8 was viewed as an iatrogenically engineered simulation of these events of ontogeny.

The argument that clonal deletion is the key mechanism of either neonatal, cytoablation, or drug-induced tolerance has not been considered defensible by Schaffner,22,23 Cohn,1 Nossal,24 and Tauber.25 If it depended solely on clonal deletion, organ transplantation was difficult to envision as a biologically sound undertaking. In fact, Burnet did not. In 1961, he wrote in the New England Journal of Medicine that “ … much thought has been given to ways by which tissues or organs not genetically and antigenically identical with the patient might be made to survive and function in the alien environment. On the whole the present outlook is highly unfavorable to success ….”26

3. THE ONE-WAY PARADIGM

3.1. Organ Transplantation

With the widespread acceptance of the simplistic one-way paradigm that emerged from the 1959–1963 period, the unidirectional in vitro tests of immune reactivity 27,28 were automatically accepted as “minitransplant models”, the results from which were assumed to be directly applicable to in vivo circumstances of transplantation. An organ allograft was envisioned as a defenseless island in a hostile sea (Figure 1 upper left). With the opposite conditions of bone marrow transplantation, histoincompatible allografts rejected the defenseless recipient (GVHD) (Figure 1 upper right).

Figure 1
(Upper panels) One-way paradigm in which transplantation is conceived as involving a unidirectional immune reaction: (left) host-versus-graft (HVG) with whole organs and (right) graft-versus-host (GVH) with bone marrow or other hematopoietic transplants. ...

The one-way paradigm guided the strategies of recipient cytoablation and “immune system replacemenC7,8 that eventually led to successful clinical bone marrow transplantation in humans,2933 a procedure that was (and is) feasible only with a perfect or good tissue (HLA) match. The belief that cytoablation (or cytoreduction) to “make microenvironmental space” was a prerequisite for leukocyte engraftment (reviewed in 34), became dogma in spite of early35,36 and recent evidence34,37 that it was not true.

To explain the differences between organ and bone marrow transplantation (Table I), it was necessary to ascribe “graft acceptance” following the two kinds of procedures to disparate mechanisms. The assumption that chimerism, the sine qua non of bone marrow transplantation, was irrelevant to an explanation of successful organ transplantation lay at the root of the dilemma.

TABLE I
Differences between conventional bone marrow and organ transplantation

4. THE TWO-WAY PARADIGM

A connection between bone marrow and organ transplantation was made in 1992 when donor leukocytes (microchimerism) were discovered up to 30 years postoperatively in the peripheral tissues or blood of human recipients of kidneys, livers, and other organs 3843 (Figure 1 lower left). The donor-derived cells were so few in number that sensitive immunocytochemical and polymerase chain reaction (PCR) techniques were required for their detection. However, we postulated that they were surviving leukocytes from one limb of originally antagonistic but ultimately reciprocally attenuated or abrogated HVG (rejection) and GVH reactions (Figure 2).

Figure 2
Comtemporaneous host versus graft (HVG) and graft versus host (GVH) reactions in the two-way paradigm as applied to organ transplantation. Following the initial interaction, the evolution of non-reactivity of each leukocyte population to the other is ...

In the first few days after organ transplantation, multilinage bone marrow derived (“passenger”) leukocytes constitute 1–20% of the host circulating mononuclear cells, depending on the kind of organ (i.e. highest with liver and intestine, lowest with heart or kidney).38,40,44 These leukocytes, which include pluripotent stem cells45,46 and dendritic cells38,4043 migrate to the recipient lymphoid organs and are largely replaced in the graft by similar recipient cells.40,41,44,4750 After about 2 weeks, small numbers of donor leukocytes can be found increasingly in other tissues and by 3 months they are mostly in non-lymphoid sites (e.g. skin and native heart).40,51,52

Thus, even with the limited information available in 1992, it was possible to suggest that organ allograft acceptance involved “… [acute] responses of co-existing donor and recipient immune cells, each to the other, causing reciprocal clonal expansion, followed by peripheral clonal deletion”.38 Much evidence has accrued subsequently in support of this bidirectional mechanism (summarized in51,52).

A second mechanism also was proposed,38,40 namely that the departure from the transplanted organ of the donor leukocytes that drive the HVG response reduces the allograft’s immunogenicity. This effect of leukocyte depletion has been demonstrated in many different experimental models.5358 For successful engraftment, the progressive change in organ immunogenicity and the clone-specific deletion of the recipient as well as donor leukocyte populations presumably take place in a close temporal relationship. In time, a stable allograft emerging from this triple process may come to resemble an immunologically neglected infection.52

5. PREVIOUS ENIGMAS

5.1. Organ Transplantation

The characteristic cycle of immunologic crisis and resolution, first observed in drug immunosuppressed kidney recipients and most practically monitored by serial changes in allograft function,16 was the product of a dual immune reaction (Figure 2). With the peripheral migration of the donor cells, and the influx of recipient cells which do not cause graft damage when adequate immunosuppression is given, both the allograft and recipient become genetic composites (Figure 1 lower left).

The mutually cancelling effect of the donor and recipient cell populations explains the rarity of GVHD following the engraftment in non-cytoablated recipients of immunologically active organs such as the intestine and liver. Disruption of the leukocyte interaction with the host cytoablation used to prepare bone marrow recipients, but not the recipients of whole organs, obviously is responsible for the differences between the two kinds of procedure (Table I) including absolute dependence on HLA matching to avoid GVHD in the first instance but not the second.

5.2. Bone Marrow Transplantation

In the context of the two-way paradigm, it can be seen that bone marrow (Figure 3) and organ transplantation (Figure 2) are, in fact, mirror images, resulting from the drastically different treatment strategies4 (Table I). This conclusion has been supported by reports describing a trace residual population of recipient leukocytes in essentially all human bone marrow recipients who previously were thought to have complete donor cell chimerism (Figure 1 lower right).59,60

Figure 3
The mirror image of Figure 2 after bone marrow transplantation to a recipient who has undergone cytoablation.

5.3. Post-Transplant Lymphoproliferative Disorders (PTLDs)

The two-way paradigm casts new light on the B cell lymphomas (PTLD) that usually are of host origin in organ recipients and of donor origin after bone marrow transplantation. Except for their frequent Epstein-Barr virus (EBV) association, these human malignancies are indistinguishable from those induced by Robert Schwartz in a mouse chimerism model61 3 years before the PTLD complication was first recognized clinically.62

Although these tumors correctly are explained in part by a loss of immune tumor surveillance,63 Schwartz attributed the development of similar neoplasms in his mouse model to the additional factor of a lymphoproliferative response by the dominant immune apparatus against the persistent subclinical GVH and immunogenicity of the minority leukocyte population. The clinical relevance of Schwartz’s observations, and of his “rules” of pathogenesis could not be appreciated until three decades later in the context of the two-way paradigm.64

6. THE “DEBATE”

Non-vital antigen can also induce donor-specific non-reactivity, albeit inefficiently and of limited duration, compared to live leukocytes.3 In the chimerism-exclusionary context of the one-way paradigm, it became axiomatic that antigens of the parenchymal (or vascular endothelial) cells of transplanted organs induced allograft acceptance by ill-defined alternative mechanisms.65 In an extension of such reasoning, it has been argued that the microchimerism associated with successful transplantation, and conversely its disappearance with or just after irreversible rejection in experimental models,6670 is epiphenomenal.71

Skepticism about the significance of microchimerism (summarized in71,72) has been based on: (1) the inconsistency with which donor leukocytes can be found in blood or tissue samples from organ recipients, (2) the development of acute or chronic rejection despite chimerism, and (3) the inability to use microchimerism to guide post-transplant drug weaning. All of these ostensibly contradictory observations can be readily fitted into the concept of the various chimeric states, providing these states are considered along with the leukocyte depletion and altered immunogenicity of the allograft. Both of these factors vary with time, and according to antigen migration and localization.52

Starzl and Zinkernagel52 have proposed that the immunologic response or non-response against infections or tumors, and under the conditions of clinical transplantation, are governed primarily by the migration and localization of antigen. In their view, immune reactivity depends on migration of antigen to organized lymphoid tissue and can be viewed as “… a balance between potentially reactive lymhocytes versus the qualities, quantity, kinetics, and distribution of the antigen (foreign or self) within the host”.52

In this context, donor leukocyte chimerism is a prerequisite for, but neither synonymous with nor a consequence of, the evolution of allograft tolerance.38,40,51,52 Although the association of chimerism with organ allograft acceptance was discounted for a third of a century,51 the principle of chimerism-linked organ allograft acceptance is no different than in the rodent neonatal,2,3 cytoablation-dependent,7,8 parabiosis-induced73 and more complicated “mixed chimerism” tolerance models7476 (Figure 4). The theme came full-circle back to the observations by Owen 77 53 years ago of natural tolerance in freemartin cattle.

Figure 4
The continuum of chimerism from observations of Ray Owen in Freemartin cattle (77) to the present. Chimerism was incorrectly discounted as a factor in organ allograft acceptance from about 1960 until the discovery in 1992 of microchimerism in organ recipients. ...

7. MECHANISMS IN THE TWO-WAY PARADIGM

The two-way paradigm defines success and failure after transplantation in a different way than before. Success implies that chimerism has been introduced which may or may not be immunosuppression-dependent. Treatment failure connotes the therapeutically uncontrollable ascendency of HVG or GVH.4,38,40,78 Pathologic evidence of both processes is found frequently in failed cases. Although the ultimate result almost always is predominantly one or the other, the two cell populations cross-modulate and are actively self-protective as a general rule. The reciprocal “defensive” mechanism is particularly important if one cell population is outnumbered and if there is severe major histocompatibility complex (MHC) dispartity.

“T-cell tolerance” is an apposite term for donor-specific non-reactivity, but it is unlikely that allograft acceptance can be fully comprehended from the results of studies of individual leukocyte phenotypes.43 The totality of events leading to tolerance suggests learning (cognitive) functions that have been explained by “networks”.7982 Network activity under the circumstances of transplantation presumably would be multimechanistically influenced by cytokines, immunoregulatory cells, antibodies, and other factors.

Considering the shifting details of signalling and effector response involved in the merger of two interactive and genetically controlled immune systems, computer modelling based on known and experimentally verifiable events may be required to fully comprehend the process. However, this level of information is not required to understand the seminal governance role of antigen migration and localization.52

8. NON-TRANSPLANT ISSUES

Transplantation does not involve unique immunologic responses.52 For example, although the relation between infectious and transplantation immunity is complicated by the presence of a double immune reaction and the additional factor of therapeutic immunosuppression after transplantation, the mechanisms and rules are basically the same and governed by antigen migration and localization. The two essential mechanisms are antigen-driven clonal exhaustion/deletion, and “indifference” of the immune system to antigen that either does not reach lymphoid organs or survives passage through them.52

Because the fetus possesses T cell immune function in the every early stages of its development,51,82,83 it can be suggested that antigen migration and localization is the basis for the ontogeny of self/non-self discrimination in the same way as it is for acquired tolerance. Autoimmune diseases would then reflect unacceptable post-natal perturbations of the prenatally established lymphoid/non-lymphoid balance (self tolerance). Thus, we have suggested an extension and modification of the meaning of “immunologic self”52 which has been enigmatic since it was described a half century ago by FM Burnet.26

9. CONCLUSION

The assumption that hematolymphopoietic chimerism was irrelevant to successful whole organ transplantation as currently practiced led to alternative inadequate explanations of organ allograft acceptance, clouded the meaning of successful bone marrow transplantation, and precluded for more than three decades the development of a cardinal principle of transplantation. Recognition of this error and the incorporation of the chimerism factor into a two-way paradigm has allowed previous enigmas of organ as well as bone marrow engraftment to be explained and may allow a better understanding of immune function generally.

References

1. Cohn M. The wisdom of hindsight. Ann Rev Immunology. 1994;12:1–62. [PubMed]
2. Billingham RE, Brent L, Medawar PB. “Actively acquired tolerance” of foreign cells. Nature. 1953;172:603–606. [PubMed]
3. Billingham R, Brent L, Medawar P. Quantitative studies on tissue transplantation immunity. III. Actively acquired tolerance. Phil Trans R Soc Lond (Biol) 1956;239:357–412. [PMC free article] [PubMed]
4. Starzl TE, Demetris AJ. Transplantation milestones: Viewed with one- and two-way paradigms of tolerance. JAMA. 1959;46:876–879. [PMC free article] [PubMed]
5. Mannick JA, Lochte HL, Ashley CA, Thomas ED, Ferrebee JW. A functioning kidney homotransplant in the dog. Surgery. 1959;46:821–828. [PubMed]
6. Hume DM, Jackson BT, Zukoski CF, Lee HM, Kauffman HM, Egdahl RH. The homotransplantation of kidneys and of fetal liver and spleen after total body irradiation. Ann Surg. 1960;152:354–373. [PubMed]
7. Main JM, Prehn RT. Successful skin homografts after the administration of high dosage X radiation and homologous bone marrow. J Natl Cancer Inst. 1995;15:1023–1029. [PubMed]
8. Trentin JJ. Mortality and skin transplantability in X-irradiated mice receiving isologous or heterologous bone marrow. Proc Soc Exper Biol Med. 1956;92:688–693. [PubMed]
9. Billingham R, Brent L. A simple method for inducing tolerance of skin homografts in mice. Trans Bull. 1957;4:67–71. [PubMed]
10. Simonsen M. The impact on the developing embryo and newborn animal of adult homologous cells. Acta Path Microbiol Scand. 1957;40:480–500. [PubMed]
11. Billingham R, Brent L. Quantitative studies on transplantation immunity. IV. Induction of tolerance in newborn mice and studies on the phenomenon of runt disease. Phil Trans R Soc Lond (Biol) 1959;242:439–477.
12. Merrill JP, Murray JE, Harrison JH, Friedman EA, Dealy JB, Jr, Dammin GJ. Successful homotransplantation of the kidney between non-identical twins. New Engl J Med. 1960;262:1251–1260.
13. Hamburger J, Vaysse J, Crosnier J, Auvert J, Lalanne CL, Hopper J., Jr Renal homotransplantation in man after radiation of the recipient. Am J Med. 1962;32:854–871. [PubMed]
14. Kuss R, Legrain M, Mathe G, Nedey R, Camey M. Homologous human kidney transplantation. Experience with six patients. Postgrad Med J. 1962;38:528–531. [PMC free article] [PubMed]
15. Murray JE, Merrill JP, Harrison JH, Wilson RE, Dammin GJ. Prolonged survival of human-kidney homografts by immunosuppressive drug therapy. New Engl J Med. 1963;268:1315–1323. [PubMed]
16. Starzl TE, Marchioro TL, Waddell WR. The reversal of rejection in human renal homografts with subsequent development of homograft tolerance. Surg Gynecol Obstet. 1963;117:385–395. [PMC free article] [PubMed]
17. Hume DM, Magee JH, Kaufmann HM, Jr, Rittenbury MS, Prout GR. Renal homotransplantation in man in modified recipients. 1963;158:642–643. [PubMed]
18. Woodruff MFA, Robson JS, Nolan B, Lambie AT, Wilson TI, Clark JG. Homotransplantation of kidney in patients treated by preoperative local irradiation and postoperative in administration of an antimetabolite (Imuran) Lancet. 1963;2:675–682. [PubMed]
19. Simonsen M. On the acquisition of tolerance by adult cells. Ann NY ACAD Science. 1960;87:382–390. [PubMed]
20. Michie D, Woodruff MFA, Zeiss IM. An investigation of immunological tolerance based on chimera analysis. Immunology. 1961;4:413–424. [PubMed]
21. Simonsen M. Graft versus host reactions. Their natural history, and applicability as tools of research. Progr Allergy. 1962;6:349–467. [PubMed]
22. Schaffner KF. Theory change in immunology, Part I: Extended theories and scientific progress. Theor Med. 1992;13:175–189. [PubMed]
23. Schaffner KF. Theory change in immunology, Part II: The clonal selection theory. Theor Med. 1992;13:191–216. [PubMed]
24. Nossal GJV. Cellular mechanisms of immunologic tolerance. Ann Rev Immunol. 1983;1:33–62. [PubMed]
25. Tauber AI. The Immune Self: Theory or Metaphor? Cambridge University Press; 1994. [PubMed]
26. Burnet FM. The new approach to immunology. N Engl J Med. 1961;264:24–34. [PubMed]
27. Bach F, Hirschhorn K. Lymphocyte interaction: A potential histocompatibility test in vitro. Science. 1964;143:813–814. [PubMed]
28. Bain B, Vas MR, Lowenstein L. The development of large immature mononuclear cells in mixed leukocyte cultures. Blood. 1964;23:108–116. [PubMed]
29. Mathe G, Amiel JL, Schwarzenberg L, Cattan A, Schneider M. Haematopoietic chimera in man after allogenic (homologous) bone marrow transplantation. Brit Med J. 1963;2:1633–1635. [PMC free article] [PubMed]
30. Gatti RA, Meuwissen HJ, Allen HD, Hong R, Good RA. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet. 1968;2:1366–1369. [PubMed]
31. Bach FH, Albertini RJ, Joo P, Anderson JL, Bortin MM. Bone-marrow transplantation in a patient with the Wiskott-Aldrich syndrome. Lancet. 1968;2:1364–1366. [PubMed]
32. Thomas ED. Allogeneic marrow grafting: A story of man and dog. In: Terasaki PI, editor. History of Transplantation: Thirty-Five Recollections. UCLA Tissue Typing Laboratory; Los Angeles, CA: 1991. pp. 379–393.
33. van Bekkum DW. Bone marrow transplantation: A story of stem cells. In: Terasaki PI, editor. History of Transplanation: Thirty-Five Recollections. UCLA Tissue Typing Laboratory; Los Angeles, CA: 1991. pp. 395–434.
34. Harrison DE. Competitive repopulation in unirradiated normal recipients. Blood. 1993;81:2473–2474. [PubMed]
35. Mariani T, Martinez C, Smith JM, Good RA. Induction of immunological tolerance to male skin isografts in female mice subsequent to neonatal period. Proc Soc Exp Biol Med. 1959;101:596–599. [PubMed]
36. Brent L, Gowland G. Induction of tolerance of skin homografts in immunologically competent mice. Nature. 1962;196:1298–1301. [PubMed]
37. Stewart FM, Crittenden RB, Lowry PA, Pearson-White S, Quesenberry PJ. Long-term engraftment of normal and post-5-fluorouracil murine marrow into normal nonmyeloablated mice. Blood. 1993;81:2566–2571. [PubMed]
38. Starzl TE, Demetris AJ, Murase N, Ildstad S, Ricordi C, Trucco M. Cell migration, chimerism, and graft acceptance. Lancet. 1992;339:1579–1582. [PMC free article] [PubMed]
39. Starzl TE, Demetris AJ, Trucco M, Ramos H, Zeevi A, Rudert WA, Kocova M, Ricordi C, Ildstad S, Murase N. Systemic chimerism in human female recipients of male livers. Lancet. 1992;340:876–877. [PMC free article] [PubMed]
40. Starzl TE, Demetris AJ, Trucco M, Murase N, Ricordi C, Ildstad S, Ramos H, Todo S, Tzakis A, Fung JJ, Nalesnik M, Rudert WA, Kocova M. Cell migration and chimerism after whole organ transplantation: The basis of graft acceptance. Hepatology. 1993;17:1127–1152. [PMC free article] [PubMed]
41. Starzl TE, Demetris AJ, Trucco M, Zeevi A, Ramos H, Terasaki P, Rudert WA, Kocova M, Ricordi C, Ildstad S, Murase N. Chimerism and donor specific nonreactivity 27 to 29 years after kidney allotransplantation. Transplantation. 1993;55:1272–1277. [PMC free article] [PubMed]
42. Starzl TE, Demetris AJ, Trucco M, Ricordi S, Ildstad S, Terasaki P, Murase N, Kendall RS, Kocova M, Rudert WA, Zeevi A, Van Thiel D. Chimerism after liver transplantation for type IV glycogen storage disease and Type I Gaucher’s disease. New Engl J Med. 1993;328:745–749. [PMC free article] [PubMed]
43. Demetris AJ, Murase N, Rao AS, Starzl TE. The role of passenger leukocytes in rejection and “tolerance” after solid organ transplantation: a potential explanation of a paradox. In: Touraine JL, editor. Rejection and Tolerance. Vol. 25. Dordrecht: Kluwer Academic Publishers; 1994. pp. 325–392.
44. Iwaki Y, Starzl TE, Yagihashi A, Taniwaki S, Abu-Elmagd K, Tzakis A, Fung J, Todo S. Replacement of donor lymphoid tissue in human small bowel transplants under FK 506 immunosuppression. Lancet. 1991;337:818–819. [PMC free article] [PubMed]
45. Murase N, Starzl TE, Ye Q, Tsamandas A, Thomson AW, Rao AS, Demetris AJ. Multilineage hematopoietic reconstitution of supralethally irradiated rats by syngeneic whole organ transplantation: with particular reference to the liver. Transplantation. 1996;61:1–3. [PMC free article] [PubMed]
46. Taniguchi H, Toyoshima T. Fukao K, Nakauchi H Presence of hematopoietic stem cells in the adult liver. Nature Medicine. 1996;2:198–203. [PubMed]
47. Kashiwagi N, Porter KA, Penn I, Brettschneider L, Starzl TE. Studies of homograft sex and of gamma globulin phenotypes after orthotopic homotransplantation of the human liver. Surg Forum. 1969;20:374–376. [PMC free article] [PubMed]
48. Porter KA. Pathology of the orthotopic homograft and heterograft. In: Starzl TE, editor. Experience In Hepatic Transplantation. Philadelphia, PA: WB Saunders Company; 1969. pp. 446–465.
49. Murase N, Demetris AJ, Matsuzaki T, Yagihasi A, Todo S, Fung J, Starzl TE. Long survival in rats after muitivisceral versus isolated small bowel allotransplantation under FK 506. Surgery. 1991;110:87–98. [PMC free article] [PubMed]
50. Starzl TE, Todo S, Tzakis A, Alessiani M, Casavilla A, Abu-Elmagd K, Fung JJ. The many faces of multivisceral transplantation. Surg Gynecol Obstet. 1991;172:335–344. [PMC free article] [PubMed]
51. Starzl TE, Demetris AJ, Murase N, Trucco M, Thomson AW, Rao AS. The lost chord: Microchimerism. Immunol Today. 1996;17:577–584. 588. [PMC free article] [PubMed]
52. Starzl TE, Zinkernagel RM. Antigen localization and migration in immunity and tolerance. New Eng J Med. in press. [PMC free article] [PubMed]
53. Steinmuller D. Immunization with skin isografts taken from tolerant mice. Science. 1967;158:127–129. [PubMed]
54. Elkins WL, Guttmann RD. Pathogenesis of a local graft versus host reaction: Immunogenicity of circulating host leukocytes. Science. 1968;159:1250, 1251. [PubMed]
55. Hart DNJ, Winearls CG, Fabre JW. Graft adaptation: studies on possible mechanisms in long-term surviving rat renal allografts. Transplantation. 1980;30:73–80. [PubMed]
56. Lechler RI, Batchelor JR. Restoration of immunogenicity to passenger cell-depleted kidney allografts by the addition of donor-strain dendritic cells. J Exp Med. 1982;155:31. [PMC free article] [PubMed]
57. Talmage DW, Dart G, Radovich J, Lafferty KJ. Activation of transplant immunity: effect of donor leukocytes on thyroid allograft rejection. Science. 1976;191:385–387. [PubMed]
58. Lafferty KJ, Prowse SJ, Simenovic CJ. Immunobiology of tissue transplantation: a return to the passenger leukocyte concept. Ann Rev Immunol. 1983;1:143–173. [PubMed]
59. Przepiorka D, Thomas ED, Durham DM, Fisher L. Use of a probe to repeat sequence of the Y chromosome for detection of host cells in peripheral blood of bone marrow transplant recipients. Am J Clin Pathol. 1991;95:201–206. [PubMed]
60. Wessman M, Popp S, Ruutu T, Volin L, Cremer T, Knuutila S. Detection of residual host cells after bone marrow transplantation using non-isotopic in situ hyubridization and karyotype analysis. Bone Marrow Transplant. 1993;11:279–284. [PubMed]
61. Schwartz R, Andre-Schwartz J. Neoplastic sequelae of allogenic disease. I. Theoretical considerations and experimental design. Ann NY Acad Sci. 1966;129:804–821.
62. Penn I, Hammond W, Brettschneider L, Starzl TE. Malignant lymphomas in transplantation patients. Transplant Proc. 1969;1:106–112. [PMC free article] [PubMed]
63. Starzl TE, Penn I, Putnam CW, Groth CG, Halgrimson CG. Iatrogenic alterations of immunologic surveillance in man and their influence on malignancy. Transplant Rev. 1971;7:112–145. [PMC free article] [PubMed]
64. Nalesnik MA, Rao AS, Furukawa H, Pham S, Zeevi A, Fung JJ, Klein G, Gritsch A, Elder E, Whiteside TL, Starzl TE. Autologous lymphokine-activated killer (LAK) cell therapy of EBV+ and EBV lymphoproliferative disorders arising in organ transplant recipients. Transplantation. 1997;63:1200–1205. [PubMed]
65. Morecki S, Leshem B, Eid A, Slavin S. Alloantigen persistence in induction and maintenance of transplantation tolerance. J Exp Med. 1987;165:1468–1480. [PMC free article] [PubMed]
66. Demetris AJ, Murase N, Fujisaki S, Fung JJ, Rao AS, Starzl TE. Hematolymphoid cell trafficking, microchimerism, and GVHD reactions after liver, bone marrow, and heart transplantation. Transplantation Proc. 1993;25:3337–3344. [PMC free article] [PubMed]
67. Murase N, Starzl TE, Tanabe M, Fujisaki S, Miyazawa H, Ye Q, Delaney CP, Fung JJ, Demetris AJ. Variable chimerism, graft versus host disease, and tolerance aftcr different kinds of cell and whole organ transplantation from Lewis to Brown-Norway rats. Transplantation. 1995;60:158–171. [PMC free article] [PubMed]
68. Murase N, Demetris AJ, Tsamandas Ac, Ye Q, Starzl TE. Heterogenous distribution of Chimerism produced by rat organ and bone marrow allotransplantation. Transplantation. 1996;61:1126–1131. [PubMed]
69. Lu L, Rudert WA, Qian S, McCaslin D, Fu F, Rao AS, Trucco M, Fung JJ, Starzl TE, Thomson AW. Growth of donor-derived dendritic cells from the bone marrow of murine liver allograft recipients in response to granulocyte/macrophage colony-stimulating factor. J Exp Med. 1995;182:379–387. [PMC free article] [PubMed]
70. Thomson AW, Lu L, Wan Y, Qian S, Larsen CP, Starzl TE. Identification of donor-derived dendritic cell progenitors in bone marrow of spontaneously tolerant liver allograft recipients. Transplantation. 1995;60:1555–1559. [PMC free article] [PubMed]
71. Bushell A, Pearson TC, Morris PJ, Wood KJ. Donor recipient microchimerism is not required for tolerance induction following recipient pretreatment with donor-specific transfusion and anti-CD4 antibody. Transplantation. 1995;59:1367–1371. [PubMed]1996;61:169–170.
72. Wood K, Sachs DH. Chimerism and transplantation tolerance: cause and effect. Immunol Today. 1996 December; In Press. [PubMed]
73. Martinez C, Shapiro F, Good RA. Essential duration of parabiosis and development of tolerance to skin homografts in mice. Proc Soc Exp Biol Med. 1960;104:256–259. [PubMed]
74. Slavin S, Strober S, Fuks Z, Kaplan HS. Induction of a specific tissue transplantation tolerance using fractionated total lymphoid irradiation tolerance using fractionated total lymphoid irradiation in adult mice: Long term survival of allogeneic bone marrow and skin grafts. J Exp Med. 1977;146:34–48. [PMC free article] [PubMed]
75. Ildstad ST, Sachs DH. Reconstitution with syngeneic plusallogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts. Nature. 1984;307:168–170. [PubMed]
76. Thomas J, Carver M, Cunningham P, Park K, Gonder J, Thomas F. Promotion of incompatible allograft acceptance in rhesus monkeys given posttransplant antithymocyte globulin and donor bone marrow. I. In vivo parameters and immunohistologic evidence suggesting microchimerism. Transplantation. 1987;43:332–338. [PubMed]
77. Owen RD. Immunogenetic consequences of vascular anastomoses between bovine twins. Science. 1945;102:400–401. [PubMed]
78. Starzl TE, Demetris AJ, Murase N, Thomson AW, Trucco M, Ricordi C. Donor cell chimerism permitted by immunosuppressive drugs: A new view of organ transplantation. Immunol Today. 1993;14:326–332. [PMC free article] [PubMed]
79. Coutinho A. Beyond clonal selection and network. Immunol Rev. 1989;110:63–87. [PubMed]
80. Cohen IR. The cognitive paradigm and the immunological homunclus. Immunol Today. 1992;13:490–494. [PubMed]
81. Waldmann H, Cobbold SP, Benjamin R, Qin S. A theorectical framework for self-tolerance as its relevance to therapy of autoimmune diseases. J Autoimmun. 1988;1:623–629.
82. Matzinger P. Tolerance, danger, and the extended family. Ann Rev Immunol. 1994;12:991–1045. [PubMed]
83. Sterzl J, Silverstein AM. Development aspects of immunity. Adv Immunol. 1967;6:337–459. [PubMed]