Rapamycin and T cell costimulatory blockade as post-transplant treatment promote fully MHC-mismatched allogeneic bone marrow engraftment under irradiation-free conditioning therapy

Wu, Tao; Sozen, H.; Luo, Bin; Heuss, Neal D.; Kalscheuer, Hannes; Lan, Ping; Sutherland, David E.R.; Hering, Bernhard J.; Guo, Zhixin

doi:10.1038/sj.bmt.1703574

Cited by 21 publications

(22 citation statements)

References 31 publications

(32 reference statements)

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“…By contrast, under the relatively stringent conditions used in our studies (no irradiation, no donor-specific transfusion, single busulfan treatment, and single BM cell transfer), the combination of anti-CD40L and everolimus was strictly synergistic, as neither reagent alone supported chimerism upon BMTx. This contrasts with reports on BMTx-induced chimerism under CD40L blockade alone, presumably owing to stronger cytoreduction or repeated BM infusion with more frequent administration of anti-CD40L (12,56,57). Several mechanisms of action were proposed for anti-CD40L, as a single agent or in combination with CTLA4Ig or rapamycin, including the induction of T regulator cells (58,59), Fc-and complement-dependent deletion (60,61), and apoptosis through costimulation blockade (10,62,63).…”

Section: Discussioncontrasting

confidence: 46%

“…Rapamycin/sirolimus was recently shown to induce hemopoietic chimerism in combination with anti-CD40L, albeit in the context of more permissive protocols that also supported chimerism with rapamycin or anti-CD40L alone (57) or with CD40L blockade alone (58). By contrast, under the relatively stringent conditions used in our studies (no irradiation, no donor-specific transfusion, single busulfan treatment, and single BM cell transfer), the combination of anti-CD40L and everolimus was strictly synergistic, as neither reagent alone supported chimerism upon BMTx.…”

Section: Discussionmentioning

confidence: 99%

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Combinations of Anti-LFA-1, Everolimus, Anti-CD40 Ligand, and Allogeneic Bone Marrow Induce Central Transplantation Tolerance through Hemopoietic Chimerism, Including Protection from Chronic Heart Allograft Rejection

Metzler

Gfeller

Bigaud

et al. 2004

The Journal of Immunology

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Central transplantation tolerance through hemopoietic chimerism initially requires inhibition of allogeneic stem cell or bone marrow (BM) rejection, as previously achieved in murine models by combinations of T cell costimulation blockade. We have evaluated LFA-1 blockade as part of regimens to support mixed hemopoietic chimerism development upon fully allogeneic BALB/c BM transfer to nonirradiated busulfan-treated B6 recipient mice. Combining anti-LFA-1 with anti-CD40 ligand (CD40L) induced high incidences and levels of stable multilineage hemopoietic chimerism comparable to chimerism achieved with anti-CD40L and everolimus (40-O-(2-hydroxyethyl)-rapamycin) under conditions where neither Ab alone was effective. The combination of anti-LFA-1 with everolimus also resulted in high levels of chimerism, albeit with a lower incidence of stability. Inhibition of acute allograft rejection critically depended on chimerism stability, even if maintained at very low levels around 1%, as was the case for some recipients without busulfan conditioning. Chimerism stability correlated with a significant donor BM-dependent loss of host-derived Vβ11+ T cells 3 mo after BM transplantation (Tx). Combinations of anti-CD40L with anti-LFA-1 or everolimus also prevented acute rejection of skin allografts transplanted before established chimerism, albeit not independently of allospecific BMTx. All skin and heart allografts transplanted to stable chimeras 3 and 5 mo after BMTx, respectively, were protected from acute rejection. Moreover, this included prevention of heart allograft vascular intimal thickening (“chronic rejection”).

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Section: Discussioncontrasting

confidence: 46%

Section: Discussionmentioning

confidence: 99%

Combinations of Anti-LFA-1, Everolimus, Anti-CD40 Ligand, and Allogeneic Bone Marrow Induce Central Transplantation Tolerance through Hemopoietic Chimerism, Including Protection from Chronic Heart Allograft Rejection

Metzler

Gfeller

Bigaud

et al. 2004

The Journal of Immunology

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“…Since we previously found that co-stimulatory blockade and rapamycin after BMT can enhance the induction of mixed chimerism (14), we hypothesized that shortterm post-transplant treatment with anti-CD154 mAb and rapamycin could suppress host-versus-graft response and promote the induction of donor chimerism under a less-intensive conditioning therapy. First, we investigated whether donor chimerism could be induced in the MHCmismatched BALB/c to C57BL/6 mouse combination by a relatively non-toxic conditioning therapy; and whether short-term post-transplant treatment with anti-CD154 mAb and rapamycin could enhance donor chimerism under cy- clophosphamide alone as conditioning therapy.…”

Section: Resultsmentioning

confidence: 99%

Increasing Donor Chimerism and Inducing Tolerance to Islet Allografts by Post-Transplant Donor Lymphocyte Infusion

Liu

Hao

Pan

et al. 2006

American Journal of Transplantation

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Inducing donor chimerism is the most consistently successful approach to achieve transplant tolerance. We found that a low level of donor chimerism, which was induced by a relatively non-toxic approach, induced donor-specific tolerance to islet allografts in chemically induced diabetic mice. However, a similar level of donor chimerism could not protect donor islet allografts in non-obese diabetic (NOD) mice that spontaneously developed autoimmune diabetes. Rejection of donor islet allografts in diabetic NOD mice with a low level of donor chimerism was mediated by recurrent autoimmunity. We used post-transplant donor lymphocyte infusion (DLI) to increase donor chimerism and to induce tolerance to islet allografts. DLI significantly increased donor chimerism and promoted donor-specific tolerance to islet allografts in diabetic NOD mice. Self-tolerance to islet autoantigens was restored and restoring self-tolerance is mediated by immunoregulation. Thus, our data showed that adoptive immunotherapy with post-transplant DLI after establishing a low level of donor chimerism as a platform enhances donor chimerism, induces donor-specific tolerance to islet allografts and restores self-tolerance in the setting of autoimmune diabetes. Our data also showed that central tolerance is not sufficient to induce tolerance and peripheral tolerance through immunoregulation for restoring self-tolerance is required in the setting of autoimmune diabetes.

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“…As regards allogeneic and, especially, xenogeneic transplantations, BU alone is not enough for a pretreatment regimen, and some additional immunosuppressive therapy must be perfomed [6,107,152,161]. The most frequently applied protocols include myeloablative agents in combination with CY or other immunosuppressive drugs, depending on the type of transplantation [29,158].…”

Section: Pretreatment Regimens Used In the Mouse Hsct Modelsmentioning

confidence: 99%

“…These regimens are usually much milder than the "classical" ones [1,116,129]. The most interesting directions of research are the new analogs of known immunosuppressive and myeloablation agents [152], costimulatory blockade [1,8,97,151], and different combinations of supra-lethal doses of irradiation and/or chemotherapeutic drugs [52,61,62,69,158]. Induction of alloantigenprimed lymphocyte depletion was recently documented to be an effective method for tolerance induction across MHC using non-myeloablative conditioning as well [93].…”

Section: Pretreatment Regimens Used In the Mouse Hsct Modelsmentioning

confidence: 99%

Key factors in experimental mouse hematopoietic stem cell transplantation

Nevozhay

Opolski

2006

Arch. Immunol. Ther. Exp.

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The first mouse model of hematopoietic stem cell transplantation (HSCT) was developed more than 50 years ago. HSCT is currently being widely used in a broad range of research areas, which include studies of the engraftment process, the pathogenesis of graft-versus-host disease and possible ways of its treatment and prophylaxis, attempts to use the graft-versus-leukemia/tumor effect in treating hematological and oncological malignancies, cancer vaccine development, induction of transplanted organ tolerance, and gene therapy. However, although this model is widely distributed, many laboratories use different protocols for the procedure. There are a number of papers discussing different HSCT protocols in clinical work, but no articles summarizing mouse laboratory models are available. This review attempts to bring together different details about HSCT in the mouse model, such as the types of transplantation, possible pretreatment regimens and their combinations, methods and sources of graft harvesting and preparation for the transplantation procedure, the influence of graft cell dose and content on the engraftment process, the transplantation method itself, possible complications, symptoms and techniques of their prophylaxis or treatment, as well as follow-up and engraftment assessment. We have also tried to reflect current knowledge of the biology of the engraftment.

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Rapamycin and T cell costimulatory blockade as post-transplant treatment promote fully MHC-mismatched allogeneic bone marrow engraftment under irradiation-free conditioning therapy

Cited by 21 publications

References 31 publications

Combinations of Anti-LFA-1, Everolimus, Anti-CD40 Ligand, and Allogeneic Bone Marrow Induce Central Transplantation Tolerance through Hemopoietic Chimerism, Including Protection from Chronic Heart Allograft Rejection

Combinations of Anti-LFA-1, Everolimus, Anti-CD40 Ligand, and Allogeneic Bone Marrow Induce Central Transplantation Tolerance through Hemopoietic Chimerism, Including Protection from Chronic Heart Allograft Rejection

Increasing Donor Chimerism and Inducing Tolerance to Islet Allografts by Post-Transplant Donor Lymphocyte Infusion

Key factors in experimental mouse hematopoietic stem cell transplantation

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