{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:36:56Z","timestamp":1791293816216,"version":"4.1.0"},"reference-count":56,"publisher":"Rockefeller University Press","issue":"4","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1997,8,18]]},"abstract":"<jats:p>The almost uniform failure in transplant patients of tolerance-inducing regimens that have been found to be effective in rodents, has made it necessary to examine large animal models before testing of new approaches clinically. Miniature swine have been shown to share many relevant immunologic parameters with humans, and because of their reproducible genetics, have proved extremely useful in providing such a large animal model. We have previously shown that indefinite systemic tolerance to renal allografts in miniature swine is induced in 100% of cases across a two-haplotype class I plus minor histocompatibility antigen disparity by a 12-d course of Cyclosporine A (CyA), in contrast to irreversible rejection observed uniformly without CyA treatment. In the present study, we have examined the role of the thymus during the induction of tolerance by performing a complete thymectomy 21 d before renal transplantation. This analysis demonstrated a striking difference between thymectomized and nonthymectomized animals. Thymectomized swine developed acute cellular rejection characterized by a T cell (CD25+) infiltrate, tubulitis, endothelialitis and glomerulitis, and anti\u2013donor CTL reactivity in vitro. Nonthymectomized and sham thymectomized animals had a mild T cell infiltrate with few CD25+ cells and no anti\u2013donor CTL response in vitro. These results indicate that the thymus is required for rapid and stable induction of tolerance.<\/jats:p>","DOI":"10.1084\/jem.186.4.497","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:49:30Z","timestamp":1027702170000},"page":"497-506","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":104,"title":["Role of the Thymus in Transplantation Tolerance in Miniature Swine. I. Requirement of the Thymus for Rapid and Stable Induction of \u2009Tolerance to Class I\u2013mismatched Renal Allografts"],"prefix":"10.1084","volume":"186","author":[{"given":"Kazuhiko","family":"Yamada","sequence":"first","affiliation":[{"name":"From the *Transplantation Biology Research Center, Massachusetts General Hospital\/Harvard Medical School, Boston, Massachusetts, 02129; and \u2021Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, 02114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre R.","family":"Gianello","sequence":"additional","affiliation":[{"name":"From the *Transplantation Biology Research Center, Massachusetts General Hospital\/Harvard Medical School, Boston, Massachusetts, 02129; and \u2021Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, 02114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco L.","family":"Ierino","sequence":"additional","affiliation":[{"name":"From the *Transplantation Biology Research Center, Massachusetts General Hospital\/Harvard Medical School, Boston, Massachusetts, 02129; and \u2021Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, 02114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Lorf","sequence":"additional","affiliation":[{"name":"From the *Transplantation Biology Research Center, Massachusetts General Hospital\/Harvard Medical School, Boston, Massachusetts, 02129; and \u2021Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, 02114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Shimizu","sequence":"additional","affiliation":[{"name":"From the *Transplantation Biology Research Center, Massachusetts General Hospital\/Harvard Medical School, Boston, Massachusetts, 02129; and \u2021Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, 02114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shane","family":"Meehan","sequence":"additional","affiliation":[{"name":"From the *Transplantation Biology Research Center, Massachusetts General Hospital\/Harvard Medical School, Boston, Massachusetts, 02129; and \u2021Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, 02114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert B.","family":"Colvin","sequence":"additional","affiliation":[{"name":"From the *Transplantation Biology Research Center, Massachusetts General Hospital\/Harvard Medical School, Boston, Massachusetts, 02129; and \u2021Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, 02114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Sachs","sequence":"additional","affiliation":[{"name":"From the *Transplantation Biology Research Center, Massachusetts General Hospital\/Harvard Medical School, Boston, Massachusetts, 02129; and \u2021Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, 02114"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[1997,8,18]]},"reference":[{"key":"2023072507342367800_B1","first-page":"115","article-title":"Enhancement of renal allografts in rats and man","volume":"13","author":"French","year":"1972","journal-title":"Transplant Rev"},{"key":"2023072507342367800_B2","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/0167-5699(93)90040-R","article-title":"The use of monoclonal antibodies to achieve immunological tolerance","volume":"14","author":"Waldmann","year":"1993","journal-title":"Immunol Today"},{"key":"2023072507342367800_B3","first-page":"406","article-title":"Prolonged survival of nonhuman primate renal allograft recipients treated only with anti-CD4 monoclonal antibody","volume":"108","author":"Cosimi","year":"1990","journal-title":"Surgery (St Louis)"},{"key":"2023072507342367800_B4","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1126\/science.1347662","article-title":"Specific acceptance of cardiac allograft after treatment with antibodies to ICAM-1 and LFA-1","volume":"255","author":"Isobe","year":"1992","journal-title":"Science (Wash DC)"},{"key":"2023072507342367800_B5","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1097\/00007890-197612000-00004","article-title":"Transplantation in miniature swine. I. Fixation of the major histocompatibility complex","volume":"22","author":"Sachs","year":"1976","journal-title":"Transplantation (Baltimore)"},{"key":"2023072507342367800_B6"},{"key":"2023072507342367800_B7","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1097\/00007890-198101000-00015","article-title":"Transplantation in miniature swine. VIII. Recombination within the major histocompatibility complex of miniature swine","volume":"31","author":"Penningtion","year":"1981","journal-title":"Transplantation (Baltimore)"},{"key":"2023072507342367800_B8","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1084\/jem.160.5.1495","article-title":"Effect of class II antigen matching on renal allograft survival in miniature swine","volume":"160","author":"Pescovitz","year":"1984","journal-title":"J Exp Med"},{"key":"2023072507342367800_B9","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1097\/00007890-199209000-00020","article-title":"Induction of specific tolerance to class I disparate renal allografts in miniature swine with cyclosporine","volume":"54","author":"Rosengard","year":"1992","journal-title":"Transplantation (Baltimore)"},{"key":"2023072507342367800_B10","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1097\/00007890-199503000-00015","article-title":"Induction of tolerance to renal allografts across single-haplotype MHC disparities in miniature swine","volume":"59","author":"Gianello","year":"1995","journal-title":"Transplantation (Baltimore)"},{"key":"2023072507342367800_B11","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1111\/j.1600-065X.1993.tb01508.x","article-title":"Tolerance to primarily vascularized allografts in miniature swine","volume":"133","author":"Gianello","year":"1993","journal-title":"Immunol Rev"},{"key":"2023072507342367800_B12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0198-8859(96)00059-6","article-title":"Effect of major histocompatability complex matching on the development of tolerance to primarily vascularized renal allografts: a study in miniature swine","volume":"50","author":"Gianello","year":"1996","journal-title":"Hum Immunol"},{"key":"2023072507342367800_B13","first-page":"1124","article-title":"Transplantation in miniature swine: acceptance of Class I antigen mismatched renal allografts","volume":"15","author":"Pescovitz","year":"1983","journal-title":"Transplant Proc"},{"key":"2023072507342367800_B14","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1097\/00007890-199403270-00003","article-title":"Retransplantation in miniature swine: graft adaptation is not required for maintenance of specific renal allograft tolerance","volume":"57","author":"Rosengard","year":"1994","journal-title":"Transplantation (Baltimore)"},{"key":"2023072507342367800_B15","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/0092-8674(87)90568-X","article-title":"T cell tolerance by clonal elimination in the thymus","volume":"49","author":"Kappler","year":"1987","journal-title":"Cell"},{"key":"2023072507342367800_B16","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/j.1600-065X.1988.tb00737.x","article-title":"T cell selection in the thymus","volume":"101","author":"Sprent","year":"1988","journal-title":"Immunol Rev"},{"key":"2023072507342367800_B17","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/332035a0","article-title":"Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex","volume":"332","author":"Kappler","year":"1988","journal-title":"Nature (Lond)"},{"key":"2023072507342367800_B18","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1126\/science.1972593","article-title":"Clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance","volume":"248","author":"Ramsdell","year":"1990","journal-title":"Science (Wash DC)"},{"key":"2023072507342367800_B19","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1111\/j.1600-065X.1993.tb01518.x","article-title":"The role of thymic epithelium in the establishment of transplantation tolerance","volume":"133","author":"Coutinho","year":"1993","journal-title":"Immunol Rev"},{"key":"2023072507342367800_B20","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1097\/00007890-199307000-00031","article-title":"Intrathymic injection of donor alloantigens induces specific tolerance to cardiac allografts","volume":"56","author":"Goss","year":"1993","journal-title":"Transplantation (Baltimore)"},{"key":"2023072507342367800_B21","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1126\/science.2119056","article-title":"Induction of donor-specific unresponsiveness by intrathymic islet transplantation","volume":"249","author":"Posselt","year":"1990","journal-title":"Science (Wash DC)"},{"key":"2023072507342367800_B22","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/0140-6736(91)91368-5","article-title":"Kidney graft survival in rats without immunosuppressants after intrathymic glomerular transplantation","volume":"337","author":"Remuzzi","year":"1991","journal-title":"Lancet (N Am Ed)"},{"key":"2023072507342367800_B23","first-page":"142","article-title":"Induction of donor-specific unresponsiveness in NIH minipigs following intrathymic islet transplantation","volume":"27","author":"Une","year":"1995","journal-title":"Transplant Proc"},{"key":"2023072507342367800_B24","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1097\/00007890-197907000-00006","article-title":"Transplantation in miniature swine. VII. Evidence for cellular immune mechanisms in hyperacute rejection of renal allografts","volume":"28","author":"Kirkman","year":"1979","journal-title":"Transplantation (Baltimore)"},{"key":"2023072507342367800_B25","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1097\/00007890-199006000-00023","article-title":"Mechanism of tolerance following class I disparate renal allografts in miniature swine: cellular responses of tolerant animals","volume":"49","author":"Kortz","year":"1990","journal-title":"Transplantation (Baltimore)"},{"key":"2023072507342367800_B26","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1038\/ki.1996.410","article-title":"The renal allograft biopsy","volume":"50","author":"Colvin","year":"1996","journal-title":"Kidney Int"},{"key":"2023072507342367800_B27","first-page":"119","article-title":"Mononuclear cells in acute allograft glomerulopathy","volume":"129","author":"Tuazon","year":"1987","journal-title":"Am J Pathol"},{"key":"2023072507342367800_B28","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/0022-1759(92)90309-H","article-title":"A monoclonal antibody recognising an epitope associated with pig interleukin-2 receptors","volume":"153","author":"Bailey","year":"1992","journal-title":"J Immunol Methods"},{"key":"2023072507342367800_B29"},{"key":"2023072507342367800_B30","doi-asserted-by":"crossref","first-page":"5249","DOI":"10.4049\/jimmunol.155.11.5249","article-title":"The human anti-porcine xenogeneic T-cell response: evidence for allelic specificity of MLR and for both direct and indirect pathways of recognition","volume":"155","author":"Yamada","year":"1995","journal-title":"J Immunol"},{"key":"2023072507342367800_B31","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/0167-5699(93)90227-C","article-title":"Characterization of swine leukocyte differentiation antigens","volume":"14","author":"Lunney","year":"1993","journal-title":"Immunol Today"},{"key":"2023072507342367800_B32","doi-asserted-by":"crossref","first-page":"368","DOI":"10.4049\/jimmunol.133.1.368","article-title":"Preparation and characterization of monoclonal antibodies reactive with porcine PBL","volume":"133","author":"Pescovitz","year":"1984","journal-title":"J Immunol"},{"key":"2023072507342367800_B33","doi-asserted-by":"crossref","first-page":"37","DOI":"10.4049\/jimmunol.134.1.37","article-title":"Murine anti-swine T4 and T8 monoclonal antibodies: distribution and effects on proliferative and cytotoxic T cells","volume":"134","author":"Pescovitz","year":"1985","journal-title":"J Immunol"},{"key":"2023072507342367800_B34","first-page":"627","article-title":"Localization of class II MHC antigens on porcine renal vascular endothelium","volume":"37","author":"Pescovitz","year":"1984","journal-title":"Transplantation (Baltimore)"},{"key":"2023072507342367800_B35","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1097\/00007890-198106000-00005","article-title":"Localization of HLA-ABC and DR antigens in human kidney","volume":"31","author":"Hart","year":"1981","journal-title":"Transplantation (Baltimore)"},{"key":"2023072507342367800_B36","doi-asserted-by":"crossref","first-page":"7","DOI":"10.4049\/jimmunol.134.1.7","article-title":"Induction of Ia antigens in murine renal transplants","volume":"134","author":"Benson","year":"1985","journal-title":"J Immunol"},{"key":"2023072507342367800_B37","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1097\/00007890-198105010-00003","article-title":"Major histocompatibility complex antigens in rat kidney, ureter, and bladder. Localization with monoclonal antibodies and demonstration of Ia-positive dendritic cells","volume":"31","author":"Hart","year":"1981","journal-title":"Transplantation (Baltimore)"},{"key":"2023072507342367800_B38","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1084\/jem.147.5.1469","article-title":"Induced immune destruction of long-surviving, H-2 incompatible kidney transplants in mice","volume":"147","author":"Russell","year":"1978","journal-title":"J Exp Med"},{"key":"2023072507342367800_B39","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1084\/jem.147.5.1449","article-title":"Kidney transplants in mice. An analysis of the immune status of mice bearing long-term, H-2 incompatible transplants","volume":"147","author":"Russell","year":"1978","journal-title":"J Exp Med"},{"key":"2023072507342367800_B40","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1097\/00007890-198712000-00006","article-title":"The role of class I and class II MHC antigens in the rejection of vascularized heart allografts in mice","volume":"44","author":"Stepkowski","year":"1987","journal-title":"Transplantation (Baltimore)"},{"key":"2023072507342367800_B41","first-page":"3303","article-title":"Rejection mechanism of class I disparate heart allografts in a rat model","volume":"21","author":"Stepkowski","year":"1989","journal-title":"Transplant Proc"},{"key":"2023072507342367800_B42","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1097\/00007890-199001000-00039","article-title":"Donor-specific cellular immunity in rejecting and long-term\u2013surviving class I\u2013disparate rat renal allograft recipients","volume":"49","author":"Ruiz","year":"1990","journal-title":"Transplantation (Baltimore)"},{"key":"2023072507342367800_B43"},{"key":"2023072507342367800_B44","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1097\/00007890-199503150-00023","article-title":"Tolerance to class I disparate renal allografts in miniature swine: maintenance of tolerance despite induction of specific antidonor CTL responses","volume":"59","author":"Gianello","year":"1995","journal-title":"Transplantation (Baltimore)"},{"key":"2023072507342367800_B45","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1097\/00007890-199507270-00001","article-title":"The role of cyclosporine-induced autoreactive T lymphocytes in solid organ allograft survival and chronic rejection","volume":"60","author":"Zhang","year":"1995","journal-title":"Transplantation (Baltimore)"},{"key":"2023072507342367800_B46","first-page":"909","article-title":"T-cell regulation of T-cell responses to antigen","volume":"26","author":"Gershon","year":"1974","journal-title":"Immunology"},{"key":"2023072507342367800_B47","first-page":"1","article-title":"T cell control of antibody production","volume":"3","author":"Gershon","year":"1974","journal-title":"Contemp Top Immunobiol"},{"key":"2023072507342367800_B48","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1084\/jem.171.1.141","article-title":"Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. III. Further characterization of the CD4+suppressor cell and its mechanisms of action","volume":"171","author":"Hall","year":"1990","journal-title":"J Exp Med"},{"key":"2023072507342367800_B49","doi-asserted-by":"crossref","first-page":"499","DOI":"10.4049\/jimmunol.143.2.499","article-title":"Mechanisms maintaining antibody-induced enhancement of allografts. II. Mediation of specific suppression by short lived CD4+T cells","volume":"143","author":"Pearce","year":"1989","journal-title":"J Immunol"},{"key":"2023072507342367800_B50","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1097\/00007890-198406000-00014","article-title":"Suppressor T cells in rats with prolonged cardiac allograft survival after treatment with Cyclosporine","volume":"37","author":"Hall","year":"1984","journal-title":"Transplantation (Baltimore)"},{"key":"2023072507342367800_B51","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1097\/00007890-198906000-00022","article-title":"Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. II. Sequential changes in alloreactivity of T cell subsets","volume":"47","author":"Hall","year":"1989","journal-title":"Transplantation (Baltimore)"},{"key":"2023072507342367800_B52","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1146\/annurev.iy.07.040189.001045","article-title":"Th1 and Th2 cells: different patterns of lymphokine secretion lead to different functional properties","volume":"7","author":"Mossman","year":"1989","journal-title":"Annu Rev Immunol"},{"key":"2023072507342367800_B53","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.4049\/jimmunol.136.7.2348","article-title":"Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins","volume":"136","author":"Mosmann","year":"1986","journal-title":"J Immunol"},{"key":"2023072507342367800_B54","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1084\/jem.170.6.2081","article-title":"Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones","volume":"170","author":"Fiorentino","year":"1989","journal-title":"J Exp Med"},{"key":"2023072507342367800_B55","doi-asserted-by":"crossref","first-page":"2800","DOI":"10.1073\/pnas.92.7.2800","article-title":"Molecular identification of porcine interleukin-10: regulation of expression in a kidney allograft model","volume":"92","author":"Blancho","year":"1995","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023072507342367800_B56","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1097\/00007890-199701150-00006","article-title":"Molecular and cellular events implicated in local tolerance to kidney allografts in miniature swine","volume":"63","author":"Blancho","year":"1997","journal-title":"Transplantation (Baltimore)"}],"container-title":["The Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/186\/4\/497\/1685372\/97-0015.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/186\/4\/497\/1685372\/97-0015.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T08:16:38Z","timestamp":1690272998000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/186\/4\/497\/7253\/Role-of-the-Thymus-in-Transplantation-Tolerance-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,8,18]]},"references-count":56,"journal-issue":{"issue":"4","published-print":{"date-parts":[[1997,8,18]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.186.4.497","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[1997,8,18]]}}}