An MHC-Defined Primate Model Reveals Significant Rejection of Bone Marrow After Mixed Chimerism Induction Despite Full MHC Matching

Larsen, Christian; Page, Andrew J.; Linzie, Kelly Hamby; Russell, Maria C.; Deane, Taylor; Stempora, Linda; Strobert, Elizabeth; Penedo, M. C. T.; Ward, Thea; Wiseman, Roger W.; O’Connor, David H.; Miller, Weston P.; Sen, Sharon; Singh, Karnail; Kean, Leslie S.

doi:10.1111/j.1600-6143.2010.03272.x

Cited by 49 publications

(120 citation statements)

References 26 publications

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“…In those studies, the recipients are preconditioned with nonmyeloablative regimens to facilitate allogeneic bone marrow engraftment. Although durable mixed chimerism was rarely achieved (Larsen et al 2010), long-term acceptance of kidney allografts in a subset of the recipients was attained (Kawai et al 1995). In a classic bench-to-bedside and then returning to the bench, efforts are now focused on identifying new ways to achieve stable mixed chimerism in the clinic, because this state resulted in the most robust form of tolerance in rodents, and also in understanding how transient chimerism favors the development of operational tolerance.…”

Section: Induction Of Central Tolerance With Mixed Chimerismmentioning

confidence: 99%

Lessons and Limits of Mouse Models

Chong

Alegre

Miller

et al. 2013

Cold Spring Harbor Perspectives in Medicine

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Seminal studies in rabbits and rodent transplantation models by Peter Medawar revealed that cellular processes, rather than humoral antibodies, are central to the acute rejection of transplanted organs, and much of basic transplantation research continues to be focused on the biology and control of these cells, which were subsequently shown to be T cells. However, the success of current immunosuppression at controlling T-cell-mediated rejection has resulted in an increasing awareness of antibody-mediated rejection in the clinic. This, in turn, has fueled an emerging interest in the biology of allospecific antibodies, the B cells that produce these antibodies, and the development of mouse models that allow their investigation. Here we summarize some of the more widely used mouse models that have been developed to study the immunobiology of alloreactivity, transplantation rejection and tolerance, and used to identify therapeutic strategies that modulate these events. R odent models in transplantation have been essential to developing a mechanistic understanding of the process of allograft rejection, as well as to the identification of novel therapeutic approaches that prevent rejection. Models of transplantation tolerance in mice and other rodents have paved the way to translational studies of tolerance induction in nonhuman primates and humans, whereas the failures in translating the successes in tolerance induction observed in mice into the clinic have led to a closer examination of the limitations of the mouse models and the identification of physiological barriers to tolerance induction. ORGAN-SPECIFIC MODELS OF ACUTE REJECTIONClinicians have long appreciated the importance of the organ type in shaping the alloreactive immune response, with lungs and small intestines having a higher propensity to being rejected compared with hearts, kidneys, or livers. Early models of organ transplantation were limited by microsurgical techniques, and the skin transplant model was extensively used. With technical advances, the heterotopic heart transplantation model is now the model of choice, although other organ transplantation models, such as kidney or liver, offer unique advantages (see Fig. 1).

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Section: Induction Of Central Tolerance With Mixed Chimerismmentioning

confidence: 99%

Lessons and Limits of Mouse Models

Chong

Alegre

Miller

et al. 2013

Cold Spring Harbor Perspectives in Medicine

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Section: Nonhuman Primate Studiesmentioning

confidence: 99%

“…Kean at Emory University demonstrated, in a novel MHC-defined rhesus monkey model, that transplantation of donor BM/mPBSCs leads to chimerism in recipients conditioned with costimulation blockade (anti-CD40L and belatacept) and nonmyeloablative busulfan treatment, but chimerism was maintained only for the length of concomitant immunosuppressive treatment with sirolimus, even in an MHCmatched donor-recipient setting [47]. Crossing a one-haplotype mismatch barrier, worsened chimerism outcome further in contrast to two MHC-haplotype matched cohorts [47]. Donor kidney grafts were rejected in the one-haplotype mismatch setting despite ongoing immunosuppression with sirolimus, anti-CD40L, and CTLA4Ig [47,48], with costimulation-blockade resistant graft rejection being linked to the accumulation of CD95+ Tmem cells [49].…”

Section: Nonhuman Primate Studiesmentioning

confidence: 99%

“…Crossing a one-haplotype mismatch barrier, worsened chimerism outcome further in contrast to two MHC-haplotype matched cohorts [47]. Donor kidney grafts were rejected in the one-haplotype mismatch setting despite ongoing immunosuppression with sirolimus, anti-CD40L, and CTLA4Ig [47,48], with costimulation-blockade resistant graft rejection being linked to the accumulation of CD95+ Tmem cells [49].A group led by Tatsuo Kawai at Havard Medical School recently showed that the use of belatacept (but not abatacept) improved the success rates of transient chimerism and renal transplant acceptance [50]. These observations were made in a cynomolgus monkey BMT model employing an irradiation-based nonmyeloablative conditioning (including TBI, thymic irradiation, antithymocyte globulin for T-cell depletion and calcineurin inhibitors) [50].…”

mentioning

confidence: 99%

“…A group led by L.S. Kean at Emory University demonstrated, in a novel MHC-defined rhesus monkey model, that transplantation of donor BM/mPBSCs leads to chimerism in recipients conditioned with costimulation blockade (anti-CD40L and belatacept) and nonmyeloablative busulfan treatment, but chimerism was maintained only for the length of concomitant immunosuppressive treatment with sirolimus, even in an MHCmatched donor-recipient setting [47]. Crossing a one-haplotype mismatch barrier, worsened chimerism outcome further in contrast to two MHC-haplotype matched cohorts [47].…”

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confidence: 99%

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Deletional and regulatory mechanisms coalesce to drive transplantation tolerance through mixed chimerism

et al. 2015

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Establishing donor-specific immunological tolerance could improve long-term outcome by obviating the need for immunosuppressive drug therapy, which is currently required to control alloreactivity after organ transplantation. Mixed chimerism is defined as the engraftment of donor hematopoietic stem cells in the recipient, leading to viable coexistence of both donor and recipient leukocytes. In numerous experimental models, cotransplantation of donor bone marrow (BM) into preconditioned (e.g., through irradiation or cytotoxic drugs) recipients leads to transplantation tolerance through (mixed) chimerism. Mixed chimerism offers immunological advantages for clinical translation; pilot trials have established proof of concept by deliberately inducing tolerance in humans.Widespread clinical application is prevented, however, by the harsh preconditioning currently necessary for permitting BM engraftment. Recently, the immunological mechanisms inducing and maintaining tolerance in experimental mixed chimerism have been defined, revealing a more prominent role for regulation than historically assumed. The evidence from murine models suggests that both deletional and regulatory mechanisms are critical in promoting complete tolerance, encompassing also the minor histocompatibility antigens. Here, we review the current understanding of tolerance through mixed chimerism and provide an outlook on how to realize widespread clinical translation based on mechanistic insights gained from chimerism protocols, including cell therapy with polyclonal regulatory T cells. Keywords: Clonal deletion Mixed chimerism Nonmyeloablative conditioning Transplantation tolerance Treg cells IntroductionLong-term outcome after organ transplantation has improved little in the past few decades and remains suboptimal [1]. Grafts are still lost to immunological damage that is not prevented by current immunosuppressive drug regimens [2], which in addition cause severe adverse effects, including increased risks of malignancy and infection. Therefore, immunological tolerance -i.e., a state of specific nonresponsiveness to donor antigens -remains the "Holy Grail" in clinical organ transplantation. Among the Correspondence: Dr. Thomas Wekerle e-mail: Thomas.Wekerle@meduniwien.ac.at numerous strategies that have been tested over time, chimerismbased tolerance induction appears particularly promising [3,4]. This concept is based on the cotransplantation of donor hematopoietic stem cells (HSCs) (contained in bone marrow (BM) or mobilized peripheral blood stem cells (mPBSCs)) into the organ transplant recipient who has been sufficiently preconditioned, either with radiation or cytotoxic drugs, to permit HSC engraftment. If engraftment is achieved, multilineage chimerism ensues, which is termed "mixed" chimerism if donor representation is clearly detectable (by flow cytometry, for instance) but is less than 100% (which would constitute "full" chimerism) and can be achieved with less extensive recipient conditioning.In 1945 Ray Owen described a naturally occur...

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