Chimerism and central tolerance

Current Opinion in Immunology

Volumn 8, Issue 5, 1996, Pages 694-703

  Sykes, Megan ^a  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CHIMERA; HEMATOPOIETIC CELL; HEMATOPOIETIC STEM CELL; HUMAN; IMMUNE SYSTEM; IMMUNOLOGICAL TOLERANCE; REVIEW; STEM CELL TRANSPLANTATION;

EID: 0030271801     PISSN: 09527915     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0952-7915(96)80088-4     Document Type: Article

References (84)

1. Auchincloss HA. Why is cell-mediated zenograft rejection so strong? Xenotransplantation. 3:1995;19-22.
2. Cobbold SP, Adams E, Marshall SE, Davies JD, Waldmann H. Mechanisms of peripheral tolerance and suppression induced by monoclonal anitbodies to CD4 and CD8. Immunol Rev. 149:1996;5-34.
3. Charlton B, Auchincloss H Jr, Fathmann CG. Mechanisms of transplantation tolerance. Annu Rev Immunol. 12:1994;707-734.
4. Matzinger P. Why positive selection? Immunol Rev. 135:1993;81-117.
5. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 12:1994;991-1045.
6. Sharabi Y, Sachs DH. Mixed chimerism and permanent specific transplantation tolerance induced by a non-lethal preparative regimen. J Exp Med. 169:1989;493-502.
7. Orloff MS, Fallon MA, DeMara E, Coppage ML, Leong N, Cerilli J. Induction of specific tolerance to small-bowel allografts. Surgery. 116:1994;222-228.
8. Webb SR, Hutchinson J, Hayden K, Sprent J. Expansion/deletion of mature T cell exposed to endogenous superantigens in vivo. J Immunol. 152:1994;586-597.
9. Rocha B, Von Boehmer H. Peripheral selection of the T cell repertoire. Science. 251:1991;1225-1228.
10. Quill H. Anergy as a mechanism of peripheral T cell tolerance. J Immunol. 156:1996;1325-1327.
11. Rocken M, Urban JF, Shevach EM. Infection breaks T cell tolerance. Nature. 359:1992;79-82.
12. Rocha B, Tanchot C, Von Boehmer H. Clonal anergy blocks in vivo growth of mature T cells and can be reversed in the absence of antigen. J Exp Med. 177:1993;1517-1521.
13. Ramsdell F, Fowlkes BJ. Maintenance of in vivo tolerance by persistence of antigen. Science. 257:1992;1130-1134.
14. Martin P. Overview of marrow transplantation immunology. Forman SJ, Blume KG, Thomas ED. Bone Marrow Transplantation. 1994;1621 Blackwell Scientific Publications, Cambridge.
15. Pierce GE, Watts LM, Clancy J Jr. Sublethal franctionated total-body irradiation and donor bone marrow infusion for induction of allograft tolerance. Transplantation. 39:1985;236-241.
16. Colson YL, Wren SM, Schuchert MJ, Patrene KD, Johnson PC, Boggs SS, Ildstad ST. A nonlethal conditioning approach to achieve durable multilineage mized chimerism and tolerance across major, minor, and hematopoletic histocompatibility barriers. J Immunol. 155:1995;4179-4188.
17. Kaufman CL, Colson YL, Wren SM, Watkins S, Simmons RL, Ildstad ST. Phenotypic characterization of a novel bone marrow derived cell that facilitates engraftment of allogeneic bone marrow stem cells. Blood. 84:1994;2436-2446.
18. Nomoto K, Yung-Yun K, Omoto K, Umesue M, Mukarami Y, Matsuzaki G. Tolerance induction in a fully allogeneic combination using anti-T cell receptor-monoclonal antibody, low dose irradiation, and donor bone marrow transfusion. Transplantation. 59:1995;395-401.
19. Sharabi Y, Sachs DH, Sykes M, Medgyesi G, Petrányi GY, Rajnavölgyi E. T cell subsets resisting inductiona of mixed chimerism across various histocompatibility barriers. Gergely J, Benczur M, Falus A, Füst GY. Progress in Immunology. VIII. 1992;801-805 Springer-Verlag, Heidelberg.
20. Vallera DA, Taylor PA, Sprent J, Blazar BR. The role of host T cell subsets in bone marrow rejection directed to isolated major histocompatibility complex class I versus class II differences of bm1 and bm12 mutant mice. Transplantation. 57:1994;249-256.
21. Lee LA, Sergio JJ, Sykes M. Natural killer cells weakly resist engraftment of allogeneic long-term multillineage-repopulating hematopoietic stem cells. Transplantation. 61:1996;125-132.
22. Sharabi Y, Aksentijevich I, Sundt TM III, Sachs DH, Sykes M. Specific tolerance induction across a xenogeneic barrier: production of mixed rat/mouse lymphohematopoietic chimeras using a nonlethal preparative regimen. J Exp Med. 172:1990;195-202.
23. of outstanding interest Kawai T, Cosimi AB, Colvin RB, Powelson J, Eason J, Kozlowski T, Sykes M, Monroy R, Tanaka M, Sachs DH. Mixed allogeneic chimerism and renal allograft tolerance in cynomologous monkeys. Transplantation. 59:1995;256-262 Reliable tolerance induction is demonstrated in a class I and class II MHC mismatched primates using low-dose WBI, thymic irradiation, and antilymphocyte serum, followed by donor marrow infusion and renal allografting, with one monthg of cyclosporine therapy. This study demonstrates that BMT can be used after nonmyeloablative conditioning to consistently induce donor-specific tolerance in primates.
24. Tomita Y, Sachs DH, Sykes M. Myelosuppressive conditioning is required to achieve to achieve engraftment of pluripotent stem cells contained in moderate doses of syngeneic bone marrow. Blood. 83:1994;939-948.
25. Ramshaw HS, Crittenden RB, Dooner M, Peters SO, Rao SS, Quesenberry PJ. High levels of engraftment with a single infusion of bone marrow cells into normal unprepared mice. Biol Blood Marrow Transplant. 1:1995;74-80.
26. Aversa F, Tabilio A, Terenzi A, Velardi A, Falzetti F, Gionnoni C, lacucci R, Zei T, Martelli MP, Gambelunghe C, et al. Successful engraftment of T-cell-depleted haploidentical three-loci incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum. Blood. 84:1994;3948-3955.
27. of special interest Bachar-Lustig E, Rachamin N, Li H-W, Lan F, Reisner Y. Megadose of T cell-depleted bone marrow overcomes MHC barriers in sublethally irradiated mice. Nat Med. 1:1995;1268-1273 It is shown that the dose of WBI required to achieve allogeneic marrow engraftment and tolerance induction can be reduced by increasing the number of allogeneic hematopoietic cells administered.
28. Petzer AL, Hagge DE, Landsdorp PM, Reid DS, Eaves CJ. Self-renewal of primitive human hematopoietic cells (long-term-culture-initiating cells) in vitro and their expansion in defined medium. Proc Natl Acad Sci USA. 93:1996;1470-1474.
29. Emerson SG. Ex vivo expansion of hematopoietic precursors, progenitors, and stem cells: the next generation of cellular therapeutics. Blood. 87:1996;3082-3088.
30. Brugger W, Heimfeld S, Berenson RJ, Mertelsmann R, Kanz L. Reconstitution of hematopoiesis after high-dose chemotherapy by autologous progenitor cells generated ex vivo. N Engl J Med. 333:1995;283-287.
31. of outstanding interest Papayannopoulou T, Craddock C, Nakamoto B, Priestley GV, Wolf NS. The VLA4/VCAM-1 adhesion pathway defines contrasting mechanisms of lodgement of transplanted murine hemopoietic progenitors between bone marrow and spleen. Proc Natl Acad Sci USA. 92:1995;9647-9651 Inhibition of the very late antigen 4/vascular cell adhesion molecule-1 (VLA4/VCAM-1) adhesion pathway is shown to mobilize and prevent the homing of hematopoietic progenitor cells to the marrow and to increase their numbers in peripheral blood and spleen. While previous in vitro studies have implicated this adhesion pathway in hematopoiesis, this is the first demonstration of its importance in vivo.
32. of special interest Lee LA, Sergio JJ, Sykes M. Evidence for non-immune mechanisms in the loss of hematopoietic chimerism in rat→mouse mixed xenogeneic chimeras. Xenotransplantation. 2:1995;57-66 Despite the gradual loss of chimerism in mixed zenogeneic chimeras prepared with a nonmyeloablative mAb-based conditioning regimen, donor-specific tolerance persists. Chimerism can be boosted long after the initial BMT with a low dose of WBI and repeat donor marrow infusion. Loss of chimerism is therefore most likely due to a nonimmune mechanism such as hematopoietic competition as the recipient recovers from irradiation. The study in [33] confirms that recipient hematopoietic cells have a competitive advantage over the xenogeneic donor in this speices combination.
33. of special interest Gritsch HA, Sykes M. Hematopoietic competition limits xenogeneic myeloid reconstitution in SCID mice. Transplant Proc. 28:1996;708 See annotation [32].
34. Lapidot T, Pflumia F, Doesdens M, Murdoch B, Williams DE, Dick Je. Cytokine stimulation of multillineage hematopoiesis from immature human cells engrated in SCID mice. Science. 255:1992;1137-1143.
35. Gritsch HA, Glaser RM, Emery DW, Lee LA, Smith CV, Sablinski T, Arn JS, Sachs DH, Sykes M. The importance of non-immune factors in reconstitution by discordant xenogeneic hematopoietic cells. Transplantation. 57:1994;906-917.
36. Yang Y-G, Sergio JJ, Swenson K, Glanser RM, Monroy R, Sykes M. Donor-specific growth factors promote swine hematopolesis in SCID mice. Xenotransplantation. 3:1996;91-101.
37. Tomita Y, Khan A, Sykes M. Role of intrathymic clonal deletion and peripheral anergy in transplantation tolerance induced by bone marrow rtransplantation in mice conditioned with a non-myeloabiative regimen. J Immunol. 153:1994;1087-1098.
38. of outstanding interest Tomita Y, Sach DH, Khan A, Sykes M. Additional mAb injections can replace thymic irradiation to allow induction of mixed chimerism and tolerance in mice receiving bone marrow transplantation after conditioning with anti-T cell mAbs and 3 Gy whole body irradiation. Transplantation. 61:1996;469-477 See annotation [39].
39. of special interest Tomita Y, Khan A, Sykes M. Mechanism by which additional monoclonal antibody injections overcome the requirement for thymic irradiation to achieve mixed chimerism in mice receiving bone marrow transplantation after conditioning with anti-T cell mAbs and 3 Gy whole body irradiation. Transplantation. 61:1996;477-485 In this paper, along with [38], it is shown that the potential toxicity of a mAb-based nonmyeloablative regimen allowing induction of mixed allogeneic chimerism and donor-specific tolerance can be further reduced by removing thymic irradiation from the conditioning regimen. Successful tolerance is induced by administration of two (instead of the standard single) CD4 and CD8 mAb injections prior to low dose WBI (3Gy) and allogeneic BMT. Intrathymic deletion is the major mechanism of tolerance in these animals, and the second mAb injection appears to inactivate residual alloreactive host thymocytes that could otherwise reject donor cells intrathymically. Such intrathymic rejection can result in the eventual loss of chimerim even if initial engraftment is achieved in the periphery.
40. of outstanding interest Ardavin C, Wu L, Li C-L, Shortman K. Thymic dendritic cells and T cells develop simultaneously in the thymus from a common precursor population. Nature. 362:1993;761-763.
41. Taniguchi Habe M, Shirai T, Fukao K, Nakauchi H. Reconstitution ratio si critical for alloreactive T cell deletion and skin graft survival in mixed bone marrow chimeras. J Immunol. 12:1995;5631-5636.
42. + T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med. 332:1995;143-149.
43. high cells and immune function within one year if chronic GVHD does not develop. This paper provides evidence that the adult thymus is functional if it is not damaged by GVHD following allogeneic BMT.
44. Lee LA, Gritsch HA, Sergio JJ, Arn JS, Glaser RM, Sablinski T, Sachs DH, Sykes M. Specific tolerance across a discordant xenogeneic transplantation barrier. Proc Natl Acad Sci USA. 91:1994;10864-10867.
45. Bonomo A, Matzinger P. Thymus epithelium induces tissue-specific tolerance. J Exp Med. 177:1993;1153-1164.
46. Martin C, Ohki-Hamazaki H, Corbel C, Coltey M, Le Douarin NM. Successful xenogeneic transplantation in embryos: induction of tolerance by extrathymic chich tissue grafted into quail. Dev Immunol. 1:1991;265-277.
47. of special interest Modigliani Y, Tomas-Vaslin V, Bandeira A, Coltey M, Le Douarin NM, Coutinho A, Salaun J. Lymphocytes selected in allogeneic thymic epithelium mediate dominant tolerance toward tissue grafts of the thymic epithelium haplotype. Proc Natl Acad Sci USA. 92:1995;7555-7559 See annotation [48].
48. of special interest Modigliani Y, Pereira P, Thomas-Vaslin V, Salaun J, Burlen-Defranoux O, Coutinho A, Le Douarin N, Bandeira A. Regulatory T cells in thymic epithelium-induced tolerance. I. Suppression of mature peripheral non-tolerant T cells. Eur J Immunol. 25:1995;2563-2571 This paper, along with [47], provides evidence that the mechanism by which pure thymic epithelial grafts, devoid fo hematopoietic cells, induce tolerance to antigens of the allogeneic thymic graft involves a mechanism other than deletion or anergy. These papers add to an increasing body of evidence that at least one mechanism by which the thymus induces tolerance is the production of an active regulatory cell population.
49. Hong R, Moore AL. Organ culture for thymus transplantation. Transplantation. 61:1996;444-448.
50. Starzl TE, Demetris AJ, Trucco M, Zeevi A, Ramos H, Terasaki P, Rudert WA, Kocova M, Ricordi C, Ildstad S, et al. Chimerism and donor-specific nonreactivity 27 to 29 years after kidney allotransplantation. Transplantation. 55:1993;1272-1277.
51. Starzl TE, Murase N, Thomson A, Demetris AJ. Liver transplants contribute to their own success. Nature Med. 2:1996;163-165.
52. of outstanding interest Burlingham WJ, Grailer AP, Fechner JH Jr, Kusaka S, Trucco M, Kocova M, Belzer FO, Solinger HW. Microchimerism linked to cytotoxic T lymphocyte functional unresponsiveness (clonal anergy) in a tolerant renal transplant recipient. Transplantation. 59:1995;1147-1155 Using repeated stimulation in the presence of interleukin-2 after depleting donor (chimeric) cells, the authors demonstrate the presence of antidonor CTLs in PBLs of a long-term renal allograft recipient who had discontinued immunosuppressive therapy. Addition of fresh recipient PBLs, however, inhibited the development of these CTLs. Removal of donor cells from patient PBLs removed the suppressive activity. This study demonstrates that donor microchimerism can actively suppress antidonor responses in a tolerant human.
53. of special interest Murase N, Starzl TE, Ye Q, Tsamandas A, Thomson AW, Rao AS, Demetris AJ. Multillineage hematopoietic reconstitution of supralethally irradiated rates by syngeneic whole organ transplantation with particular reference to the liver. Transplantation. 61:1996;1-4 See annotation [54].
54. of special interest Taniguchi H, Toyoshima T, Fukao K, Nakauchi H. Presence of hematopoietic stem cells in the adult liver. Nat Med. 2:1996;198-203 This paper, along with [53], demonstrates that adult rat and mouse livers, respectively, contain sufficient hematopoietic cells to protect animals from death due to irradiation-induced aplasia. The latter paper also demonstrates the presence of cells with the phenotype of pluripotent stem cells in the adult mouse liver. These studies provide a basis for the possibility that long-term chimerism in liver graft recipients is due to ongoing differentiation from self-renewing hematopoietic progenitors or stem cells derived from the organ graft.
55. of special interest Lu L, Rudert WA, Qian SG, McCaslin D, Fu RM, 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 is response to granulocyte/macrophage colony-stimulating factor. J Exp Med. 182:1995;379-387 This study demonstrates the presence of cells in recipient marrow of donor derived progenitors that could potentially be involved in tolerance induction.
56. of outstanding interest 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. 59:1995;1367-1371 The role of chimerism is examined when murine cardiac allograft tolerance is facilitated by prior donor-specific transfusion and CD4 mAbs. It is demonstrated that repeated injection, for a limited time period, of irradiated donor specific transfusions is as effective as a single untreated donor-specific transfusion at facilitating tolerance induction. Thus, the authors conclude that lasting chimerism from the donor-specific transfusion is not required for the maintenance of tolerance in this model.
57. of outstanding interest Alard P, Matriano JA, Socarras S, Ortega M-A, Streilein JW. Detection of donor-derived cells by polymerase chain reaction in neonatally tolerant mice. Microchimerism fails to predict tolerance. Transplantation. 60:1995;1125-1130 Microchimerism is shown to be present at the time of skin grafting in mice that received neonatal hematopoietic cell injections that failed to induce skin graft tolerance. This is an important demonstration tha the presence of microchimerism is insufficient in itself to maintain tolerance in animals receiving hematopoietic cell injections without suppression of the pre-existing immune system. Chimerism persists even after skin graft rejection, suggesting that surviving donor hematopoietic cells may be resistant to destruction by host T-cells, but are insufficient ot maintain systemic tolerance.
58. Fisher RA, Cohen DS, Ben-Ezra JM, Sallade RE, Tawes JW, Tarry WC. Induction of long-term graft tolerance and donor/recipient chimerism. J Surg Res. 60:1996;181-185.
59. Reinsmoen NL, Jackson A, McSherry C, Ninova D, Wiesner RH, Kondo M, Krom RAF, Hertz MI, Bolman RM III, Matas AJ. Organ-specific patterns of donor antigen-specific hyporeactivity and peripheral blood allogeneic microchimerism in lung kidney, and liver transplant recipients. Transplantation. 60:1995;1546-1554.
60. of special interest Shapiro R, Rao AS, Fontes P, Zeevi A, Jordan M, Scantlebury VP, Vivas C, Gritsch HA, Corry RJ, Egidi F, et al. Combined simultaneous kidney/bone marrow transplantation. Transplantation. 60:1995;1421-1425 Despite increased levels of early chimerism no difference has been seen thus far in the outcome of allograting when donor bone marrow is administered with standard immunosuppression, without specific myelosuppression. These data suggest that in humans, as in rodents, the mere presence of chimerism is insufficient to ensure a state of tolerance; specific conditions must be established under which chimerism can lead to tolerance.
61. Thomas JM, Verbanac KM, Smith JP, Kasten-Jolly J, Gross U, Rebellato LM, Haisch CE, Carver FM, Thomas FT. The facilitating effect of one-DR antigen sharing in renal allograft toleracne induced by donor bone marrow in rhesus monkeys. Transplantation. 59:1995;245-255.
62. Rolles K, Burroughs AK, Davidson BR, Karatapanis S, Prentice HG, Hamon MD. Donor-specific bone marrow infusion after orthotopic liver transplantation. Lancet. 343:1994;263-265.
63. Verbanac KM, Carver FM, Haisch CE, Thomas JM. The role for transforming growth factor-beta in the veto mechanism in transplant tolerance. Transplantation. 57:1994;893-900.
64. Streilein JW. Neonatal tolerance of H-2 alloantigens. Transplantation. 52:1991;1-10.
65. of special interest Chen N, Field EH. Enhanced type 2 and diminished type 1 cytokines in neonatal tolerance. Transplantation. 59:1995;933-941 Tis si shown that acceptance of skin grafts from the strain to which animals had been neonatally tolerized is associated with increased interleukin-4 and decreased interferon-γ production, whereas rejection of a third party graft leads to predominant interferon-γ production. This result suggests that neonatal tolerance may be due to immune diviation toward a Th2-like response that may prevent graft rejection by inhibiting Th1 responses.
66. of outstanding interest Donckier V, Wissing M, Bruyns C, Abramowicz D, Lybin M, Vanderhaeghen M-L, Goldman M. Critical role of interleukin 4 in the induction of neonatal transplantation tolerance. Transplantation. 59:1995;1571-1576 It is shown that neutralization of interleukin-4 prevents neonatal tolerance induction, and permits development of Th1 cytokine responses. This result implicates interleukin-4 and Th2 responses in the induction of neonatal tolerance.
67. Smith JP, Kasten-Jolly J, Field LJ, Thomas JM. Assessment of donro bone marrow cell-derived chimerism in transplantation tolerance using transgenic mice. Transplantation. 58:1994;324-329.
68. Hedrick MH, Rice HE, MacGilivray TE, Bealer JF, Zanjani ED, Flake AW. Hematopoietic chimerism achieved by in utero hematopoietic stem cell injection does not induce donor-specific tolerance for renal allografts in sheep. Transplantation. 58:1994;110-111.
69. of outstanding interest Ridge JP, Fuchs EJ, Matzinger P. Neonatal tolerance revisited: turning on newborn T cells with dendritic cells. Science. 271:1996;1723-1726 This study demonstrates that the immune system of the neonate does not have any special propensity toward tolerance induction upon alloantigen exposure. Instead, the animals are shown to be capable of mounting anti-H-Y CTL responses if exposed in the neonatal period to an appropriately immunogenic type of APC expressing male-specific H-Y minor antigens. The authors conclude that the relative ease with which neonatal mice are rendered tolerant to antigens compared to adult mice is due to the high ratio of tolerogenic APCs (T and B cells) to recipient T cells to which the neonates are exposed. Exposure of adults to a similar APC population in similar ratio to total recipient T cell number has the same outcome as in neonates.
70. of outstanding interest Sarzotti M, Robbins DS, Hoffman PM. Induction of protective CTL responses in newborn mice by a murine retrovirus. Science. 271:1996;1726-1728 It is shown that the apparent inability of neonatal mice to mount CTL responses to a virus is due to the relatively high dose of virus used, which leads to a Th2 response. When lower viral doses are administered, the neonate mounts a Th1 response, which results in CTL development.
71. of outstanding interest Forsthuber T, Yip HC, Lehmann PV. Induction of Th1 and Th2 immunity in neonatal mice. Science. 271:1996;1728-1730 It is shown that neonates do not have a special propensity to develop Th2 responses upon exposure to antigen. If exposed to protein antigen in an appropriately immunogenic fashion, neonates are quite capable of mounting Th1 responses.
72. Sykes M, Sheard MA, Sachs DH. Effects of T cell depletion in radiation bone marrow chimeras. II. Requirement for allogeneic T cells in the reconstituting bone marrow inoculum for subsequent resistance to breaking of tolerance. J Exp Med. 168:1988;661-673.
73. of outstanding interest Khan A, Tomita Y, Sykes M. Thymic dependence of loss of tolerance in mixed allogeneic bone marrow chimeras after depletion of donor antigen. Peripheral mechanisms do not to maintenance of tolerance. Transplantation. 1996; The ability to break tolerance in mixed allogeneic chimeras by eliminating chimerism with mAbs administered in vivo is shown to require a host thymus. Tolerance persists in the absence of antigen if the thymus is removed. Tolerance is readily broken by infusion of notolerant host-type lymphocytes. These results indicate that in mixed allogeneic chimeras produced by a nonmyeloablative regimen that adequately eliminates the pre-existing T cell repertoire, the maintenance of tolerance is due to ongoing intrathymic deletion, with no significant contribution form the mechanisms of anergy or suppression.
74. Roser BJ. Cellular mechanisms in neonatal and adult tolerance. Immunol Rev. 107:1989;179-202.
75. Lubaroff DM, Silvers WK. The importance of chimerism in maintaining tolerance of skin allografts in mice. J Immunol. 111:1973;65-71.
76. Gianello PR, Yamada K, Fishbein JM, Lorf T, Nickeleit V, Colvin RB, Arn JS, Sachs DH. Long-term acceptance of primarily vascularized renal allografts in miniature swine. Transplantation. 61:1996;503-522.
77. Agus DB, Surh CD, Sprent J. Reentry of T cells to the adult thymus is restricted to activated T cells. J Exp Med. 173:1991;1039-1046.
78. Blancho G, Gianello P, Germana S, Baetscher M, Sachs DH, LeGuem C. Molecular identification of porcine interleukin 10: regulation of expression in a kidney allograft model. Proc Natl Acad Sci USA. 92:1995;2800-2804.
79. + suppressor cells on the presence of alloantigen and cytokines, including interleukin-2. Transplantation. 55:1993;374-379.
80. Oluwole SF, Jin M-X, Chowdhury NC, Ohajewkwe OA. Effectiveness of intrathymic inoculation of soluble antigens in the induction of specific unresponsiveness to rat islet allografts without transient recipient immunosuppression. Transplantation. 58:1994;1077-1081.
81. Sayegh MH, Perico N, Gallon L, Imberti O, Hancock WW, Remuzzi G, Carpenter CB. Mechanisms of acquired thymic unresponsiveness to renal allografts. Thymic recognition of immunodominant allo-MHC peptides induces peripheral T cell anergy. Transplantation. 58:1994;125-132.
82. Odorico JS, OConnor T, Campos L, Barker CF, Posselt AM, Naji A. Examination of the mechanisms responsible for tolerance induction after intrathymic inoculation of allogeneic bone marrow. Ann Surg. 218:1993;525-531.
83. of special interest Debruin RWF, Vanrossum TJ, Scheringa M, Bonthuis F, Ljzermans JNM, Marquet RL. Intrathymic injection of alloantigen may lead to hyperacute rejection and prolonged graft survival of heart allografts in the rat. Transplantation. 60:1996;1061-1063 See annotation [84].
84. of special interest Alfrey EJ, Wang X, Lee L, Holm B, Kim J, Adams G, DaFoe DC. Tolerance induced by direct inoculation of donor antigen into the thymus in low and high responder rodents. Transplantation. 59:1995;1171-1176 This reference, along with [83], shows that the induction of tolerance versus sensitization by the intrathymic injection of alloantigen is dependent or the strenght of the alloresponse between the strain combination examined. These results suggest that a better understanding of the mechanism by which this approach can induce tolerance is needed in order to find reliable predictors of its potential efficacy in humans.