FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2020672759> ?p ?o ?g. }

• W2020672759 endingPage "424" @default.
• W2020672759 startingPage "417" @default.
• W2020672759 abstract "Induction of specific immunologic tolerance to donor antigens would avoid both chronic graft rejection and the side effects associated with chronic, nonspecific immunosuppressive therapy. It has been known for many years that hematopoietic chimerism, when established in preimmune animals, leads to transplantation tolerance. Exposure of the developing immune system to donor antigen results in education of the immune system to regard the donor as “self.” Achieving a similar outcome in recipients with an established immune system presents additional challenges, as it requires ablation or tolerization of the preexisting immune system. Immunoablation and myeloablation with lethal total body irradiation (TBI) allows reconstitution with allogeneic hematopoietic cells and induction of transplantation tolerance in adult rodents (reviewed in Wekerle and Sykes 1999Wekerle T. Sykes M. Mixed chimerism as an approach for the induction of transplantation tolerance.Transplantation. 1999; 68: 459-467Crossref PubMed Scopus (120) Google Scholar). Such animals are referred to as “full” hematopoietic chimeras. In contrast, “mixed” chimerism refers to a state in which allogeneic hematopoietic cells coexist with recipient cells. Mixed chimerism can be induced in adult mice by reconstituting lethally irradiated animals with a mixture of T cell–depleted allogeneic and host-type marrow, by administering allogeneic marrow following treatment with high doses of total lymphoid irradiation, or with non-myeloablative regimens (see below). In such animals, specific tolerance to donor tissue grafts and host antigens is produced (reviewed in Wekerle and Sykes 1999Wekerle T. Sykes M. Mixed chimerism as an approach for the induction of transplantation tolerance.Transplantation. 1999; 68: 459-467Crossref PubMed Scopus (120) Google Scholar). There are several advantages of mixed chimerism over full chimerism as an approach to the induction of transplantation tolerance. One is that mixed chimerism can be achieved with non-myeloablative regimens, which are generally less toxic than myeloablative conditioning, as is discussed further below. A second advantage is the superior immunocompetence of mixed compared to full chimeras produced across complete MHC barriers. If a tolerance-inducing protocol is to be practicable for cadaveric organ transplantation, then it must be successful across complete histocompatibility barriers, since HLA matching is highly impractical in this situation. However, induction of full chimerism across complete MHC barriers may be associated with immunoincompetence resulting from the full MHC disparity between the positive selecting elements in the thymus, which are of host origin, and the antigen-presenting cells (APC) in the periphery, which are entirely of donor origin in full chimeras. These T cells are ineffective at mounting relevant donor-restricted immune responses and lack host APC that could induce generation of host-restricted responses. In contrast, mixed chimeras have a lifelong source of host APC to allow effective generation of host-restricted immune responses (reviewed in Wekerle and Sykes 1999Wekerle T. Sykes M. Mixed chimerism as an approach for the induction of transplantation tolerance.Transplantation. 1999; 68: 459-467Crossref PubMed Scopus (120) Google Scholar). Although the premise that hematopoietic cells do not participate in positive selection is controversial and has recently been challenged (Zinkernagel and Althage 1999Zinkernagel R.M. Althage A. On the role of thymic epithelium vs. bone marrow-derived cells in repertoire selection of T cells.Proc. Natl. Acad. Sci. USA. 1999; 96: 8092-8097Crossref PubMed Scopus (74) Google Scholar), studies of anti-viral CTL responses in mixed chimeras showed exquisite specificity for recipient-derived MHC restricting elements (Ruedi et al. 1989Ruedi E. Sykes M. Ildstad S.T. Chester C.H. Althage A. Hengartner H. Sachs D.H. Zinkernagel R.M. Antiviral T cell competence and restriction specificity of mixed allogeneic (P1+P2→P1) irradiation chimeras.Cell. Immunol. 1989; 121: 185-195Crossref PubMed Scopus (64) Google Scholar). In mixed chimeras, hematopoietic cells from both the recipient and the donor locate to the thymus and hence delete both host-reactive and donor-reactive T cells, resulting in a peripheral T cell repertoire that is tolerant toward the donor and the host (Tomita et al. 1994aTomita Y. Khan A. Sykes M. Role of intrathymic clonal deletion and peripheral anergy in transplantation tolerance induced by bone marrow transplantation in mice conditioned with a non-myeloablative regimen.J. Immunol. 1994; 153 (a): 1087-1098PubMed Google Scholar, Manilay et al. 1998aManilay J.O. Pearson D.A. Sergio J.J. Swenson K.G. Sykes M. Intrathymic deletion of alloreactive T cells in mixed bone marrow chimeras prepared with a nonmyeloablative conditioning regimen.Transplantation. 1998; 66 (a): 96-102Crossref PubMed Scopus (138) Google Scholar). This results in a third advantage of mixed over full chimerism. Although nonhematopoietic thymic stromal cells have some capacity to induce deletional tolerance, the capacity of hematopoietic cells, especially dendritic cells, to do so is particularly powerful. Thus, because there are host- as well as donor-derived hematopoietic APC in the thymi of mixed (but not full) chimeras, intrathymic deletion of host-reactive cells in addition to donor-reactive cells occurs in mixed chimeras to a greater extent than in full chimeras (Yoshikai et al. 1990Yoshikai Y. Ogimoto M. Matsuzaki G. Nomoto K. Bone marrow-derived cells are essential for intrathymic deletion of self-reactive T cells in both the host- and donor-derived thymocytes of fully allogeneic bone marrow chimeras.J. Immunol. 1990; 145: 505-509PubMed Google Scholar, Tomita et al. 1994aTomita Y. Khan A. Sykes M. Role of intrathymic clonal deletion and peripheral anergy in transplantation tolerance induced by bone marrow transplantation in mice conditioned with a non-myeloablative regimen.J. Immunol. 1994; 153 (a): 1087-1098PubMed Google Scholar). While there are clearly other mechanisms by which host-reactive T cells can be tolerized in this setting, tolerance due to T cell “anergy” can be broken under certain conditions (Ramsdell and Fowlkes 1992Ramsdell F. Fowlkes B.J. Maintenance of in vivo tolerance by persistence of antigen.Science. 1992; 257: 1130-1134Crossref PubMed Scopus (200) Google Scholar), whereas T cells deleted in the thymus stand no chance of causing pathology under any circumstance. Since deletional tolerance is particularly robust, host-versus-graft tolerance induced in this way allows acceptance of highly immunogenic primary skin or small bowel grafts across the most extensive histocompatibility barriers (reviewed in Wekerle and Sykes 1999Wekerle T. Sykes M. Mixed chimerism as an approach for the induction of transplantation tolerance.Transplantation. 1999; 68: 459-467Crossref PubMed Scopus (120) Google Scholar). Other types of grafts, such as primarily vascularized hearts and kidneys, are tolerogenic in rodents but unfortunately may be less so in large animals. Indeed, there are many successful protocols for inducing tolerance to heart, kidney, and liver allografts in rodents. It appears that giving sufficient immunosuppression to inhibit the initial rejection of the graft allows the inherently tolerogenic properties of these allografts to ultimately prevail. The tolerance is often erroneously attributed to the initial treatment that was given to the recipient, rather than to the primarily vascularized allograft. Unfortunately, efforts to translate such protocols into large animals have usually failed. Information on the molecular mechanisms of tolerance induced by nondeletional mechanisms is just beginning to emerge, making it far more difficult to translate these complex phenomena into the clinic. In view of differences between species in the actions, toxicities, and dose responses of various drugs and biological agents, without a clear understanding of exactly what pathways are relevant and without clear markers of the tolerant state it is very difficult to translate such approaches to human recipients. In contrast, successful engraftment of donor marrow has been associated with transplantation tolerance in large animals (Kawai et al. 1995Kawai T. Cosimi A.B. Colvin R.B. Powelson J. Eason J. Kozlowski T. Sykes M. Monroy R. Tanaka M. Sachs D.H. Mixed allogeneic chimerism and renal allograft tolerance in cynomologous monkeys.Transplantation. 1995; 59: 256-262Crossref PubMed Scopus (484) Google Scholar, Fuchimoto et al. 2000Fuchimoto Y. Huang C.A. Yamada K. Shimizu A. Kitamura H. Colvin R.B. Ferrara V. Murphy M.C. Sykes M. White-Scharf M. et al.Mixed chimerism and tolerance without whole body irradiation in a large animal model.J. Clin. Invest. 2000; 105: 1779-1789Crossref PubMed Scopus (165) Google Scholar, Huang et al. 2000Huang C.A. Fuchimoto Y. Sheir-Dolberg R. Murphy M.C. Neville Jr., D.M. Sachs D.H. Stable mixed chimerism and tolerance using a non-myeloablative preparative regimen in a large animal model.J. Clin. Invest. 2000; 105: 173-181Crossref PubMed Scopus (177) Google Scholar) and humans (reviewed in Dey et al. 1998Dey B. Sykes M. Spitzer T.R. Outcomes of combined bone marrow and solid organ transplants a review.Medicine. 1998; 77: 355-369Crossref PubMed Scopus (94) Google Scholar). As might be expected, tolerance induced by intrathymic deletional mechanisms is systemic, as shown by both in vivo and in vitro studies (reviewed in Wekerle and Sykes 1999Wekerle T. Sykes M. Mixed chimerism as an approach for the induction of transplantation tolerance.Transplantation. 1999; 68: 459-467Crossref PubMed Scopus (120) Google Scholar). While anergy may play a role in tolerizing the few peripheral T cells that escape depletion with mAbs in some protocols (Tomita et al. 1994aTomita Y. Khan A. Sykes M. Role of intrathymic clonal deletion and peripheral anergy in transplantation tolerance induced by bone marrow transplantation in mice conditioned with a non-myeloablative regimen.J. Immunol. 1994; 153 (a): 1087-1098PubMed Google Scholar), long-term tolerance appears to be maintained purely by a deletional mechanism. Using donor MHC-specific antibody to eliminate donor chimerism from established mixed chimeras leads to a loss of tolerance and to the de novo appearance in the periphery of T cells with Vβ that recognize superantigens presented by the donor. However, if the recipient thymus is removed prior to elimination of chimerism with antibody, specific tolerance to the donor is preserved, and donor-reactive TCR do not appear in the periphery (Khan et al. 1996Khan 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 contribute to maintenance of tolerance.Transplantation. 1996; 62: 380-387Crossref PubMed Scopus (146) Google Scholar). Thus, chimerism is needed only in the thymus and not in the periphery in order to ensure persistent tolerance. This is consistent with a purely deletional mechanism, since anergy and suppression generally require the relevant antigen to maintain the tolerance. The result also demonstrates that the thymus is sufficiently functional in senescent mice to generate donor-reactive T cells if donor antigen is not continuously present in the thymus. Since thymic APC are continually turning over, this emphasizes the need for true hematopoietic stem cell engraftment at sufficient levels in order to ensure an uninterrupted supply of donor APC in the recipient thymus for the life of the mixed chimera. The absence of suppressive tolerance mechanisms makes them particularly vulnerable to breaking of tolerance when nontolerant T cells emerge from the thymus after intentional depletion of donor antigen or after exogenous administration of nontolerant host-type T cells (Khan et al. 1996Khan 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 contribute to maintenance of tolerance.Transplantation. 1996; 62: 380-387Crossref PubMed Scopus (146) Google Scholar). Despite the advantages described above, induction of mixed chimerism has not yet been routinely applied in human recipients of organ grafts. Application of hematopoietic cell transplantation (HCT) for tolerance induction in humans has been largely prohibited by the toxicity of the host conditioning traditionally used to allow allogeneic marrow engraftment and by the formidable problem of GVHD encountered when even partial HLA barriers were transgressed. While GVHD can be ameliorated by donor marrow T cell depletion, this approach increases the incidence of failure of marrow engraftment, which can cause fatal aplasia in myeloablated recipients. In recent years, however, an evolving understanding of the minimal requirements for achievement of lasting chimerism have moved the mixed chimerism approach to tolerance induction toward clinical application. These requirements are summarized in Figure 1, and their delineation began with the demonstration that fully MHC-mismatched marrow engraftment and specific tolerance could be achieved by pretreating recipients with depleting doses of anti-CD4 and anti-CD8 mAbs along with a sublethal dose (6 Gy) of total body irradiation (TBI) (Cobbold et al. 1986Cobbold S.P. Martin G. Qin S. Waldmann H. Monoclonal antibodies to promote marrow engraftment and tissue graft tolerance.Nature. 1986; 323: 164-165Crossref PubMed Scopus (319) Google Scholar) or even with a minimally myelosuppressive (Tomita et al. 1994bTomita Y. Sachs D.H. Sykes M. Myelosuppressive conditioning is required to achieve engraftment of pluripotent stem cells contained in moderate doses of syngeneic bone marrow.Blood. 1994; 83 (b): 939-948PubMed Google Scholar) dose of TBI (3 Gy), if additional selective irradiation was given to the thymic area (referred to as thymic irradiation [TI]) (Sharabi and Sachs 1989Sharabi Y. Sachs D.H. Mixed chimerism and permanent specific transplantation tolerance induced by a non-lethal preparative regimen.J. Exp. Med. 1989; 169: 493-502Crossref PubMed Scopus (560) Google Scholar). TI is needed to overcome residual alloreactivity that persists in the thymus (Nikolic et al. 2001bNikolic B. Cooke D.T. Zhao G. Sykes M. Both γ/δ T cells and NK cells inhibit the engraftment of xenogeneic rat bone marrow cells in mice.J. Immunol. 2001; 166 (b): 1398-1404PubMed Google Scholar), since mAb doses that effectively deplete peripheral T cells are insufficient to deplete alloreactive thymocytes (Nikolic et al. 2001aNikolic B. Khan A. Sykes M. Induction of tolerance by mixed chimerism with nonmyeloablative host conditioning the imperative of overcoming intrathymic alloresistance.Biol. Blood Marrow Transplant. 2001; in press (a)Google Scholar) (Figure 1). TI also creates some hematopoietic “space,” leading to increased donor pluripotent stem cell engraftment, and additionally increases the intrathymic engraftment of thymocyte progenitors, which appears to be under separate regulation from engraftment in the marrow compartment (Sykes et al. 1998Sykes M. Szot G.L. Swenson K. Pearson D.A. Wekerle T. Separate regulation of peripheral hematopoietic and thymic engraftment.Exp. Hematol. 1998; 26: 457-465PubMed Google Scholar). Because the conditioning regimen does not ablate the recipient's hematopoietic system (Sharabi and Sachs 1989Sharabi Y. Sachs D.H. Mixed chimerism and permanent specific transplantation tolerance induced by a non-lethal preparative regimen.J. Exp. Med. 1989; 169: 493-502Crossref PubMed Scopus (560) Google Scholar, Tomita et al. 1994bTomita Y. Sachs D.H. Sykes M. Myelosuppressive conditioning is required to achieve engraftment of pluripotent stem cells contained in moderate doses of syngeneic bone marrow.Blood. 1994; 83 (b): 939-948PubMed Google Scholar) and hence is referred to as “non-myeloablative,” a state of mixed hematopoietic chimerism is achieved when allogeneic marrow engrafts. Recently, a number of modifications have made these conditioning regimens even less toxic. These include the replacement of TI with a second injection of depleting anti-T cell mAbs (reviewed in Wekerle and Sykes 1999Wekerle T. Sykes M. Mixed chimerism as an approach for the induction of transplantation tolerance.Transplantation. 1999; 68: 459-467Crossref PubMed Scopus (120) Google Scholar), with pretransplant CYA treatment (Nikolic et al. 2000Nikolic B. Zhao G. Swenson K. Sykes M. A novel application of cyclosporine A in nonmyeloablative pretransplant host conditioning for allogeneic BMT.Blood. 2000; 96: 1166-1172PubMed Google Scholar), or with a costimulatory blocker (Wekerle et al. 1999bWekerle T. Sayegh M.H. Ito H. Hill J. Chandraker A. Pearson D.A. Swenson K.G. Zhao G. Sykes M. Anti-CD154 or CTLA4Ig obviates the need for thymic irradiation in a non-myeloablative conditioning regimen for the induction of mixed hematopoietic chimerism and tolerance.Transplantation. 1999; 68 (b): 1348-1355Crossref PubMed Scopus (104) Google Scholar). Both TI and host T cell depleting mAbs can be omitted by using costimulatory blockade (Wekerle et al. 1998Wekerle T. Sayegh M.H. Hill J. Zhao Y. Chandraker A. Swenson K.G. Zhao G. Sykes M. Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is followed by central T cell tolerance.J. Exp. Med. 1998; 187: 2037-2044Crossref PubMed Scopus (292) Google Scholar). TBI can be omitted by administering very high marrow doses (reviewed in Wekerle and Sykes 1999Wekerle T. Sykes M. Mixed chimerism as an approach for the induction of transplantation tolerance.Transplantation. 1999; 68: 459-467Crossref PubMed Scopus (120) Google Scholar), and all preconditioning can be eliminated by giving a high dose of fully MHC-mismatched donor marrow followed by a single injection of each of two costimulatory blockers (Wekerle et al. 2000Wekerle T. Kurtz J. Ito H. Ronquillo J.V. Dong V. Zhao G. Shaffer J. Sayegh M.H. Sykes M. Allogeneic bone marrow transplantation with costimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment.Nat. Med. 2000; 6: 464-469Crossref PubMed Scopus (439) Google Scholar) or repeated injections of anti-CD40 ligand (Durham et al. 2000Durham M.M. Bingaman A.W. Adams A.B. Ha J. Waitze S.Y. Pearson T.C. Larsen C.P. Cutting edge administration of anti-CD40 ligand and donor bone marrow leads to hemopoietic chimerism and donor-specific tolerance without cytoreductive conditioning.J. Immunol. 2000; 165: 1-4PubMed Google Scholar). Apparently, the administration of very large hematopoietic cell doses can overcome the requirement to create space with myelosuppressive treatment in order to achieve marrow engraftment (Stewart et al. 1993Stewart F.M. Crittenden R.B. Lowry P.A. Pearson-White S. Quesenberry P.J. Long-term engraftment of normal and post-5-fluorouracil murine marrow into normal nonmyeloablated mice.Blood. 1993; 81: 2566-2571PubMed Google Scholar, Sykes et al. 1998Sykes M. Szot G.L. Swenson K. Pearson D.A. Wekerle T. Separate regulation of peripheral hematopoietic and thymic engraftment.Exp. Hematol. 1998; 26: 457-465PubMed Google Scholar) (Figure 1). The ability to replace recipient T cell depletion with costimulatory blockade is encouraging for several reasons. First, it has been difficult to achieve T cell depletion with antibodies in large animals and humans that is as exhaustive as that achieved in the above rodent models, perhaps due to the use of inadequate doses or suboptimal reagents. A second concern is that, if sufficiently exhaustive T cell depletion could be achieved in humans, T cell recovery from the thymus might be dangerously slow, especially in older individuals. With increasing age, the adult human thymus becomes progressively more sluggish in achieving immune reconstitution after ablative treatments or with antiretroviral therapy in patients with HIV infection (reviewed in Haynes et al. 2000Haynes B.F. Markert M.L. Sempowski G.D. Patel D.D. Hale L.P. The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection.Annu. Rev. Immunol. 2000; 18: 529-560Crossref PubMed Scopus (408) Google Scholar). However, it is also clear that normal adults do have thymic function, even in old age (Haynes et al. 2000Haynes B.F. Markert M.L. Sempowski G.D. Patel D.D. Hale L.P. The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection.Annu. Rev. Immunol. 2000; 18: 529-560Crossref PubMed Scopus (408) Google Scholar), and the capacity for regeneration and “rebound” thymopoiesis in an individual whose thymus has not been subjected to injury by the above agents is largely unknown. Nevertheless, it would clearly be desirable to minimize the degree and duration of T cell depletion used in protocols for the induction of mixed chimerism. The ability to do this by replacing some (Ito et al. 2001Ito H. Kurtz J. Shaffer J. Sykes M. CD4 T cell-mediated alloresistance to fully MHC-mismatched allogeneic bone marrow engraftment is dependent on CD40-CD40L interactions, and lasting T cell tolerance is induced by bone marrow transplantation with initial blockade of this pathway.J. Immunol. 2001; in pressGoogle Scholar) or all (Wekerle et al. 1998Wekerle T. Sayegh M.H. Hill J. Zhao Y. Chandraker A. Swenson K.G. Zhao G. Sykes M. Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is followed by central T cell tolerance.J. Exp. Med. 1998; 187: 2037-2044Crossref PubMed Scopus (292) Google Scholar, Wekerle et al. 2000Wekerle T. Kurtz J. Ito H. Ronquillo J.V. Dong V. Zhao G. Shaffer J. Sayegh M.H. Sykes M. Allogeneic bone marrow transplantation with costimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment.Nat. Med. 2000; 6: 464-469Crossref PubMed Scopus (439) Google Scholar, Durham et al. 2000Durham M.M. Bingaman A.W. Adams A.B. Ha J. Waitze S.Y. Pearson T.C. Larsen C.P. Cutting edge administration of anti-CD40 ligand and donor bone marrow leads to hemopoietic chimerism and donor-specific tolerance without cytoreductive conditioning.J. Immunol. 2000; 165: 1-4PubMed Google Scholar) of the T cell depleting antibodies with a single injection of costimulatory blockers is therefore of considerable interest. While long-term tolerance is maintained by intrathymic deletion in mixed chimeras prepared with costimulatory blockade (Wekerle et al. 1998Wekerle T. Sayegh M.H. Hill J. Zhao Y. Chandraker A. Swenson K.G. Zhao G. Sykes M. Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is followed by central T cell tolerance.J. Exp. Med. 1998; 187: 2037-2044Crossref PubMed Scopus (292) Google Scholar, Wekerle et al. 2000Wekerle T. Kurtz J. Ito H. Ronquillo J.V. Dong V. Zhao G. Shaffer J. Sayegh M.H. Sykes M. Allogeneic bone marrow transplantation with costimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment.Nat. Med. 2000; 6: 464-469Crossref PubMed Scopus (439) Google Scholar, Ito et al. 2001Ito H. Kurtz J. Shaffer J. Sykes M. CD4 T cell-mediated alloresistance to fully MHC-mismatched allogeneic bone marrow engraftment is dependent on CD40-CD40L interactions, and lasting T cell tolerance is induced by bone marrow transplantation with initial blockade of this pathway.J. Immunol. 2001; in pressGoogle Scholar), the mechanisms of initial tolerance in animals receiving BMT under cover of costimulatory blockade instead of T cell depletion are not fully understood. Large numbers of alloreactive T cells present in the peripheral lymphoid tissues of these animals must be tolerized. Peripheral deletion of donor-reactive cells through a combination of activation-induced cell death and “passive cell death” appears to play a role (Wekerle et al. 1998Wekerle T. Sayegh M.H. Hill J. Zhao Y. Chandraker A. Swenson K.G. Zhao G. Sykes M. Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is followed by central T cell tolerance.J. Exp. Med. 1998; 187: 2037-2044Crossref PubMed Scopus (292) Google Scholar, Wekerle et al. 2000Wekerle T. Kurtz J. Ito H. Ronquillo J.V. Dong V. Zhao G. Shaffer J. Sayegh M.H. Sykes M. Allogeneic bone marrow transplantation with costimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment.Nat. Med. 2000; 6: 464-469Crossref PubMed Scopus (439) Google Scholar, Wekerle et al. 2001Wekerle T. Kurtz J. Sayegh M.H. Ito H. Wells A.D. Bensinger S. Shaffer J. Turka L.A. Sykes M. Peripheral deletion after bone marrow transplantation with costimulatory blockade has features of both activation-induced cell death and passive cell death.J. Immunol. 2001; 166: 2311-2316PubMed Google Scholar). However, donor-specific tolerance is complete in mixed lymphocyte reactions by 1 week posttransplant, when deletion of donor-reactive CD4 cells is only partial (J. Kurtz et al., submitted), suggesting that mechanisms in addition to deletion are involved in the early tolerization of peripheral CD4 cells by donor bone marrow in the presence of costimulatory blockade. Although attractive because they do not require host T cell depletion, one limitation to the use of costimulatory blockade in place of peripheral T cell depletion to achieve allogeneic bone marrow engraftment is that it is not 100% successful, i.e., a fraction of animals fails to achieve permanent chimerism or donor-specific skin graft acceptance (Wekerle et al. 1998Wekerle T. Sayegh M.H. Hill J. Zhao Y. Chandraker A. Swenson K.G. Zhao G. Sykes M. Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is followed by central T cell tolerance.J. Exp. Med. 1998; 187: 2037-2044Crossref PubMed Scopus (292) Google Scholar, Wekerle et al. 2000Wekerle T. Kurtz J. Ito H. Ronquillo J.V. Dong V. Zhao G. Shaffer J. Sayegh M.H. Sykes M. Allogeneic bone marrow transplantation with costimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment.Nat. Med. 2000; 6: 464-469Crossref PubMed Scopus (439) Google Scholar). Either CTLA4Ig or anti-CD154 mAb overcame the requirement for thymic irradiation or repeated injection of T cell–depleting antibodies in mice receiving a T cell depletion regimen that was in itself insufficient to permit induction of lasting chimerism (Wekerle et al. 1999bWekerle T. Sayegh M.H. Ito H. Hill J. Chandraker A. Pearson D.A. Swenson K.G. Zhao G. Sykes M. Anti-CD154 or CTLA4Ig obviates the need for thymic irradiation in a non-myeloablative conditioning regimen for the induction of mixed hematopoietic chimerism and tolerance.Transplantation. 1999; 68 (b): 1348-1355Crossref PubMed Scopus (104) Google Scholar). In fact, a single injection of anti-CD40L mAb is sufficient to allow BMT to induce tolerance of CD4 cells in mice receiving an injection of depleting anti-CD8 mAb (Ito et al. 2001Ito H. Kurtz J. Shaffer J. Sykes M. CD4 T cell-mediated alloresistance to fully MHC-mismatched allogeneic bone marrow engraftment is dependent on CD40-CD40L interactions, and lasting T cell tolerance is induced by bone marrow transplantation with initial blockade of this pathway.J. Immunol. 2001; in pressGoogle Scholar). The anti-CD40L mAb is required only to block the interaction between CD40L and CD40 and not to target activated T cells for depletion or to signal to the CD4 cell (J. Kurtz et al., submitted). These results indicate that CD4 cell-mediated alloresistance to bone marrow grafts is exquisitely dependent on CD40–CD40L interactions. This is somewhat surprising, since CD40-independent pathways can activate APC to induce antiviral CD4 cell responses. Much remains to be learned about the mechanisms by which CD4 T cells are tolerized to alloantigens when APC activation via CD40 is blocked. GVHD does not occur in the rodent models discussed above, despite the use of unseparated donor bone marrow cells (BMC). This is most readily explained by the continued presence of the T cell–depleting or costimulatory blocking antibodies in the serum of the hosts at the time of BMT (Tomita et al. 1996Tomita 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. 1996; 61: 477-485Crossref PubMed Scopus (66) Google Scholar). These levels are sufficient to prevent alloreactivity by the relatively small number of mature T cells in the donor marrow. A donor-specific transfusion (DST) model is of particular interest for comparison to the mixed chimerism model, since both models involve the use of hematopoietic cells in the presence of costimulatory blockade, but only the mixed chimerism model allows engraftment of hematopoietic stem cells and intrathymic deletion as a mechanism maintaining tolerance in the long term (Wekerle et al. 1999bWekerle T. Sayegh M.H. Ito H. Hill J. Chandraker A. Pearson D.A. Swenson K.G. Zhao G. Sykes M. Anti-CD154 or CTLA4Ig obviates the need for thymic irradiation in a non-myeloablative conditioning regimen for the induction of mixed hematopoietic chimerism and tolerance.Transplantation. 1999; 68 (b): 1348-1355Crossref PubMed Scopus (104) Google Scholar, Wekerle et al. 2000Wekerle T. Kurtz J. Ito H. Ronquillo J.V. Dong V. Zhao G. Shaffer J. Sayegh M.H. Sykes M. Allogeneic bone marrow transplantation with costimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment.Nat. Med. 2000; 6: 464-469Crossref PubMed Scopus (439) Google Scholar). Indeed, DST and anti-CD40L allows long-term" @default.
• W2020672759 created "2016-06-24" @default.
• W2020672759 creator A5061151796 @default.
• W2020672759 date "2001-04-01" @default.
• W2020672759 modified "2023-10-11" @default.
• W2020672759 title "Mixed Chimerism and Transplant Tolerance" @default.
• W2020672759 cites W11344094 @default.
• W2020672759 cites W1493759757 @default.
• W2020672759 cites W1494432631 @default.
• W2020672759 cites W1496757932 @default.
• W2020672759 cites W1498934814 @default.
• W2020672759 cites W1508187469 @default.
• W2020672759 cites W1520847221 @default.
• W2020672759 cites W1532325696 @default.
• W2020672759 cites W1535382400 @default.
• W2020672759 cites W1548356984 @default.
• W2020672759 cites W1581554632 @default.
• W2020672759 cites W1591644649 @default.
• W2020672759 cites W193978997 @default.
• W2020672759 cites W1946143675 @default.
• W2020672759 cites W1967891950 @default.
• W2020672759 cites W1968118657 @default.
• W2020672759 cites W1968616022 @default.
• W2020672759 cites W1969797237 @default.
• W2020672759 cites W1975853381 @default.
• W2020672759 cites W1979518727 @default.
• W2020672759 cites W1981284886 @default.
• W2020672759 cites W1983329640 @default.
• W2020672759 cites W1989484846 @default.
• W2020672759 cites W2003176999 @default.
• W2020672759 cites W2003657878 @default.
• W2020672759 cites W2013571030 @default.
• W2020672759 cites W2019291297 @default.
• W2020672759 cites W2023492750 @default.
• W2020672759 cites W2024518035 @default.
• W2020672759 cites W2024604633 @default.
• W2020672759 cites W2028537846 @default.
• W2020672759 cites W2032415838 @default.
• W2020672759 cites W2050198445 @default.
• W2020672759 cites W2054083392 @default.
• W2020672759 cites W2054870010 @default.
• W2020672759 cites W2056210319 @default.
• W2020672759 cites W2063288953 @default.
• W2020672759 cites W2065128134 @default.
• W2020672759 cites W2065271434 @default.
• W2020672759 cites W2068653310 @default.
• W2020672759 cites W2088962680 @default.
• W2020672759 cites W2090992688 @default.
• W2020672759 cites W2098790859 @default.
• W2020672759 cites W2110176131 @default.
• W2020672759 cites W2113586042 @default.
• W2020672759 cites W2114814098 @default.
• W2020672759 cites W2118637098 @default.
• W2020672759 cites W2125379033 @default.
• W2020672759 cites W2126845096 @default.
• W2020672759 cites W2127576269 @default.
• W2020672759 cites W2128983927 @default.
• W2020672759 cites W2132829945 @default.
• W2020672759 cites W2136693778 @default.
• W2020672759 cites W2137151166 @default.
• W2020672759 cites W2138868414 @default.
• W2020672759 cites W2140916758 @default.
• W2020672759 cites W2141825306 @default.
• W2020672759 cites W2142010842 @default.
• W2020672759 cites W2150841203 @default.
• W2020672759 cites W2151817322 @default.
• W2020672759 cites W2152918507 @default.
• W2020672759 cites W2170451898 @default.
• W2020672759 cites W2338963113 @default.
• W2020672759 cites W2413131581 @default.
• W2020672759 doi "https://doi.org/10.1016/s1074-7613(01)00122-4" @default.
• W2020672759 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/11336687" @default.
• W2020672759 hasPublicationYear "2001" @default.
• W2020672759 type Work @default.
• W2020672759 sameAs 2020672759 @default.
• W2020672759 citedByCount "370" @default.
• W2020672759 countsByYear W20206727592012 @default.
• W2020672759 countsByYear W20206727592013 @default.
• W2020672759 countsByYear W20206727592014 @default.
• W2020672759 countsByYear W20206727592015 @default.
• W2020672759 countsByYear W20206727592016 @default.
• W2020672759 countsByYear W20206727592017 @default.
• W2020672759 countsByYear W20206727592018 @default.
• W2020672759 countsByYear W20206727592019 @default.
• W2020672759 countsByYear W20206727592021 @default.
• W2020672759 countsByYear W20206727592022 @default.
• W2020672759 countsByYear W20206727592023 @default.
• W2020672759 crossrefType "journal-article" @default.
• W2020672759 hasAuthorship W2020672759A5061151796 @default.
• W2020672759 hasBestOaLocation W20206727591 @default.
• W2020672759 hasConcept C203014093 @default.
• W2020672759 hasConcept C70721500 @default.
• W2020672759 hasConcept C86803240 @default.
• W2020672759 hasConceptScore W2020672759C203014093 @default.
• W2020672759 hasConceptScore W2020672759C70721500 @default.
• W2020672759 hasConceptScore W2020672759C86803240 @default.
• W2020672759 hasIssue "4" @default.
• W2020672759 hasLocation W20206727591 @default.

• next