{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T15:13:39Z","timestamp":1790435619793,"version":"4.1.0"},"reference-count":45,"publisher":"Rockefeller University Press","issue":"12","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1998,6,15]]},"abstract":"<jats:p>A reliable, nontoxic method of inducing transplantation tolerance is needed to overcome the problems of chronic organ graft rejection and immunosuppression-related toxicity. Treatment of mice with single injections of an anti-CD40 ligand antibody and CTLA4Ig, a low dose (3 Gy) of whole body irradiation, plus fully major histocompatibility complex\u2013mismatched allogeneic bone marrow transplantation (BMT) reliably induced high levels (&amp;gt;40%) of stable (&amp;gt;8 mo) multilineage donor hematopoiesis. Chimeric mice permanently accepted donor skin grafts (&amp;gt;100 d), and rapidly rejected third party grafts. Progressive deletion of donor-reactive host T cells occurred among peripheral CD4+ lymphocytes, beginning as early as 1 wk after bone marrow transplantation. Early deletion of peripheral donor-reactive host CD4 cells also occurred in thymectomized, similarly treated marrow recipients, demonstrating a role for peripheral clonal deletion of donor-reactive T cells after allogeneic BMT in the presence of costimulatory blockade. Central intrathymic deletion of newly developing T cells ensued after donor stem cell engraftment had occurred. Thus, we have shown that high levels of chimerism and systemic T cell tolerance can be reliably achieved without myeloablation or T cell depletion of the host. Chronic immunosuppression and rejection are avoided with this powerful, nontoxic approach to inducing tolerance.<\/jats:p>","DOI":"10.1084\/jem.187.12.2037","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:49:30Z","timestamp":1027702170000},"page":"2037-2044","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":280,"title":["Extrathymic T Cell Deletion and Allogeneic Stem Cell Engraftment Induced with Costimulatory Blockade Is Followed by Central T Cell Tolerance"],"prefix":"10.1084","volume":"187","author":[{"given":"Thomas","family":"Wekerle","sequence":"first","affiliation":[{"name":"From the *Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 02129; and the \u2021Laboratory of Immunogenetics and Transplantation, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed H.","family":"Sayegh","sequence":"additional","affiliation":[{"name":"From the *Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 02129; and the \u2021Laboratory of Immunogenetics and Transplantation, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Hill","sequence":"additional","affiliation":[{"name":"From the *Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 02129; and the \u2021Laboratory of Immunogenetics and Transplantation, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Zhao","sequence":"additional","affiliation":[{"name":"From the *Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 02129; and the \u2021Laboratory of Immunogenetics and Transplantation, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anil","family":"Chandraker","sequence":"additional","affiliation":[{"name":"From the *Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 02129; and the \u2021Laboratory of Immunogenetics and Transplantation, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten G.","family":"Swenson","sequence":"additional","affiliation":[{"name":"From the *Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 02129; and the \u2021Laboratory of Immunogenetics and Transplantation, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiling","family":"Zhao","sequence":"additional","affiliation":[{"name":"From the *Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 02129; and the \u2021Laboratory of Immunogenetics and Transplantation, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Sykes","sequence":"additional","affiliation":[{"name":"From the *Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 02129; and the \u2021Laboratory of Immunogenetics and Transplantation, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[1998,6,15]]},"reference":[{"key":"2023072507411357700_B1"},{"key":"2023072507411357700_B2","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1146\/annurev.iy.11.040193.001203","article-title":"The role of the CD28 receptor during T cell responses to antigen","volume":"11","author":"Linsley","year":"1993","journal-title":"Annu Rev Immunol"},{"key":"2023072507411357700_B3","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1084\/jem.181.5.1869","article-title":"CD28-B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2","volume":"181","author":"Sayegh","year":"1995","journal-title":"J Exp Med"},{"key":"2023072507411357700_B4","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1146\/annurev.immunol.14.1.591","article-title":"Immune regulation by CD40 and its ligand gp39","volume":"14","author":"Foy","year":"1996","journal-title":"Annu Rev Immunol"},{"key":"2023072507411357700_B5","doi-asserted-by":"crossref","first-page":"13967","DOI":"10.1073\/pnas.93.24.13967","article-title":"Costimulatory function of CD40L, CD80 and CD86 in vascularized murine cardiac allograft rejection","volume":"93","author":"Hancock","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023072507411357700_B6","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/S0952-7915(97)80043-X","article-title":"The CD40 pathway in allograft rejection, acceptance, and tolerance","volume":"9","author":"Larsen","year":"1997","journal-title":"Curr Opin Immunol"},{"key":"2023072507411357700_B7","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1126\/science.1323143","article-title":"Long-term survival of xenogeneic pancreatic islets induced by CTLA4Ig","volume":"257","author":"Lenshow","year":"1992","journal-title":"Science"},{"key":"2023072507411357700_B8","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1097\/00007890-199457120-00002","article-title":"Transplantation tolerance induced by CTLA4Ig","volume":"57","author":"Pearson","year":"1994","journal-title":"Transplantation"},{"key":"2023072507411357700_B9","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1097\/00007890-199707270-00026","article-title":"Prolonged survival of mouse skin allografts in recipients treated with donor splenocytes and antibody to CD40 ligand","volume":"64","author":"Markees","year":"1997","journal-title":"Transplantation"},{"key":"2023072507411357700_B10","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1126\/science.1496399","article-title":"Immunosuppression in vivo by a soluble form of the CTLA-4 T\u2002cell activation molecule","volume":"257","author":"Linsley","year":"1992","journal-title":"Science"},{"key":"2023072507411357700_B11","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/381434a0","article-title":"Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways","volume":"381","author":"Larsen","year":"1996","journal-title":"Nature"},{"key":"2023072507411357700_B12","doi-asserted-by":"crossref","first-page":"8789","DOI":"10.1073\/pnas.94.16.8789","article-title":"CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates","volume":"94","author":"Kirk","year":"1997","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023072507411357700_B13"},{"key":"2023072507411357700_B14","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1016\/S0952-7915(96)80088-4","article-title":"Chimerism and central tolerance","volume":"8","author":"Sykes","year":"1996","journal-title":"Curr Opin Immunol"},{"key":"2023072507411357700_B15","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/0092-8674(94)90331-X","article-title":"Negative selection of lymphocytes","volume":"76","author":"Nossal","year":"1994","journal-title":"Cell"},{"key":"2023072507411357700_B16","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/172603a0","article-title":"\u201cActively acquired tolerance\u201d of foreign cells","volume":"172","author":"Billingham","year":"1953","journal-title":"Nature"},{"key":"2023072507411357700_B17","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1084\/jem.171.3.645","article-title":"In vivo administration of interleukin 2 plus T cell\u2013 depleted syngeneic marrow prevents graft-versus-host disease mortality and permits alloengraftment","volume":"171","author":"Sykes","year":"1990","journal-title":"J Exp Med"},{"key":"2023072507411357700_B18","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1084\/jem.169.2.493","article-title":"Mixed chimerism and permanent specific transplantation tolerance induced by a non-lethal preparative regimen","volume":"169","author":"Sharabi","year":"1989","journal-title":"J Exp Med"},{"key":"2023072507411357700_B19","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/bjc.1960.11","article-title":"Studies on mouse leukaemia: the role of the thymus in leukaemagenesis by cell-free leukemic infiltrates","volume":"14","author":"Miller","year":"1960","journal-title":"Br J Cancer"},{"key":"2023072507411357700_B20","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1084\/jem.178.1.223","article-title":"Hematopoietic cells and radioresistant host elements influence natural killer cell differentiation","volume":"178","author":"Sykes","year":"1993","journal-title":"J Exp Med"},{"key":"2023072507411357700_B21","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1097\/00007890-199602150-00027","article-title":"Additional monoclonal antibody (mAB) injections can replace thymic irradiation to allow induction of mixed chimerism and tolerance in mice receiving bone marrow transplantation after conditioning with anti\u2013T cell mABs and 3-Gy whole body irradiation","volume":"61","author":"Tomita","year":"1996","journal-title":"Transplantation"},{"key":"2023072507411357700_B22","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1084\/jem.150.3.580","article-title":"Characterization of a monoclonal antibody directed against mouse macrophage and lymphocyte Fc receptors","volume":"150","author":"Unkeless","year":"1979","journal-title":"J Exp Med"},{"key":"2023072507411357700_B23","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.4049\/jimmunol.153.3.1087","article-title":"Role of intrathymic clonal deletion and peripheral anergy in transplantation tolerance induced by bone marrow transplantation in mice conditioned with a non-myeloablative regimen","volume":"153","author":"Tomita","year":"1994","journal-title":"J Immunol"},{"key":"2023072507411357700_B24","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1097\/00007890-199602150-00028","article-title":"Mechanism by which additional monoclonal antibody (mAB) injections overcome the requirement for thymic irradiation to achieve mixed chimerism in mice receiving bone marrow transplantation after conditioning with anti\u2013T cell mABs and 3-Gy whole body irradiation","volume":"61","author":"Tomita","year":"1996","journal-title":"Transplantation"},{"key":"2023072507411357700_B25","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/307168a0","article-title":"Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts","volume":"307","author":"Ildstad","year":"1984","journal-title":"Nature"},{"key":"2023072507411357700_B26","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1097\/00007890-199502150-00015","article-title":"Tolerance induction in a fully allogeneic combination using anti\u2013T cell receptor-\u03b1\u03b2 monoclonal antibody, low dose irradiation, and donor bone marrow transfusion","volume":"59","author":"Nomoto","year":"1995","journal-title":"Transplantation"},{"key":"2023072507411357700_B27","doi-asserted-by":"crossref","first-page":"2820","DOI":"10.4049\/jimmunol.157.7.2820","article-title":"Durable mixed allogeneic chimerism and tolerance by a nonlethal radiation-based cytoreductive approach","volume":"157","author":"Colson","year":"1996","journal-title":"J Immunol"},{"key":"2023072507411357700_B28","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1084\/jem.169.1.213","article-title":"Long-lasting skin allograft tolerance in adult mice induced across fully allogeneic (multimajor H-2 plus multiminor histocompatibility) antigen barriers by a tolerance-inducing method using cyclophosphamide","volume":"169","author":"Mayumi","year":"1989","journal-title":"J Exp Med"},{"key":"2023072507411357700_B29","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1056\/NEJM199501193320303","article-title":"Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy","volume":"332","author":"Mackall","year":"1995","journal-title":"N Engl J Med"},{"key":"2023072507411357700_B30","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.4049\/jimmunol.160.5.2059","article-title":"IFN-\u03b3 is critical for long-term allograft survival induced by blocking the CD28 and CD40 ligand T cell costimulation pathways","volume":"160","author":"Konieczny","year":"1998","journal-title":"J Immunol"},{"key":"2023072507411357700_B31","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/0167-5699(91)90066-3","article-title":"Mls\u2014a retrovirus exploits the immune system","volume":"12","author":"Acha-Orbea","year":"1991","journal-title":"Immunol Today"},{"key":"2023072507411357700_B32","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/BF01719234","article-title":"The genetic basis of negative selection of Tcr\u03b2-V11\u03b2+ T cells","volume":"33","author":"Tomonari","year":"1991","journal-title":"Immunogenetics"},{"key":"2023072507411357700_B33","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/349531a0","article-title":"Genes encoding ligands for deletion of V\u03b211 T cells cosegregate with mammary tumour virus genomes","volume":"349","author":"Dyson","year":"1991","journal-title":"Nature"},{"key":"2023072507411357700_B34","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1084\/jem.169.4.1405","article-title":"The MHC molecule I-E is necessary but not sufficient for the clonal deletion of V\u03b211-bearing T cells","volume":"169","author":"Bill","year":"1989","journal-title":"J Exp Med"},{"key":"2023072507411357700_B35","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1084\/jem.178.5.1567","article-title":"In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. II. Prolonged suppression of the humoral immune response by an antibody to the ligand for CD40, gp39","volume":"178","author":"Foy","year":"1993","journal-title":"J Exp Med"},{"key":"2023072507411357700_B36","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1084\/jem.178.5.1555","article-title":"In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. I. In vivo expression of CD40 ligand, cytokines, and antibody production delineates sites of cognate T\u2013B cell interactions","volume":"178","author":"Van den Eertwegh","year":"1993","journal-title":"J Exp Med"},{"key":"2023072507411357700_B37","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1182\/blood.V83.4.939.939","article-title":"Myelosuppressive conditioning is required to achieve engraftment of pluripotent stem cells contained in moderate doses of syngeneic bone marrow","volume":"83","author":"Tomita","year":"1994","journal-title":"Blood"},{"key":"2023072507411357700_B38","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1016\/0092-8674(90)90420-J","article-title":"Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity","volume":"63","author":"Webb","year":"1990","journal-title":"Cell"},{"key":"2023072507411357700_B39","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/349245a0","article-title":"Programmed cell death and extrathymic reduction in V\u03b28+ CD4+ T cells in mice tolerant to Staphylococcus aureusenterotoxin B","volume":"349","author":"Kawabe","year":"1991","journal-title":"Nature"},{"key":"2023072507411357700_B40","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/1074-7613(95)90161-2","article-title":"CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-xL","volume":"3","author":"Boise","year":"1995","journal-title":"Immunity"},{"key":"2023072507411357700_B41","doi-asserted-by":"crossref","first-page":"636","DOI":"10.4049\/jimmunol.157.2.636","article-title":"CD28 costimulation prevents cell death during primary T cell activation","volume":"157","author":"Noel","year":"1996","journal-title":"J Immunol"},{"key":"2023072507411357700_B42","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.4049\/jimmunol.156.5.1788","article-title":"CD28 costimulation inhibits TCR-induced apoptosis during a primary T cell response","volume":"156","author":"Radvanyi","year":"1996","journal-title":"J Immunol"},{"key":"2023072507411357700_B43","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1084\/jem.167.6.2005","article-title":"Intrathymic elimination of Mlsa-reactive (V\u03b26+) cells during neonatal tolerance induction to Mlsa-encoded antigens","volume":"167","author":"MacDonald","year":"1988","journal-title":"J Exp Med"},{"key":"2023072507411357700_B44","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1084\/jem.170.6.1947","article-title":"Capacity of unprimed CD4+ and CD8+T cells expressing V\u03b211 receptors to respond to I-E alloantigens in vivo","volume":"170","author":"Gao","year":"1989","journal-title":"J Exp Med"},{"key":"2023072507411357700_B45","doi-asserted-by":"crossref","first-page":"9560","DOI":"10.1073\/pnas.92.21.9560","article-title":"Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligand","volume":"92","author":"Parker","year":"1995","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["The Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/187\/12\/2037\/1686138\/98-0151.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/187\/12\/2037\/1686138\/98-0151.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T08:25:53Z","timestamp":1690273553000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/187\/12\/2037\/7422\/Extrathymic-T-Cell-Deletion-and-Allogeneic-Stem"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1998,6,15]]},"references-count":45,"journal-issue":{"issue":"12","published-print":{"date-parts":[[1998,6,15]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.187.12.2037","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[1998,6,15]]}}}