Efficacy of Transient Treatment with FK506 in the Early Phase on Cyclophosphamide-Induced Bone Marrow Chimerism and Transplant Tolerance across MHC Barriers

Okayama, Junji; Ko, Saiho; Kanehiro, Hiromichi; Kanokogi, Hideki; Nakajima, Yoshiyuki

doi:10.1016/j.jss.2005.10.012

Cited by 2 publications

(3 citation statements)

References 30 publications

(22 reference statements)

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“…In a number of these models, engraftment, reconstitution, chimerism, cell trafficking, and tolerance toward donor cells has been studied (Clancy et al, 1983; Oaks and Cramer, 1985; Ohajekwe et al, 1995; Engh et al, 2001; Foster et al, 2001; Okayama et al, 2004; Itakura et al, 2007; Klimczak et al, 2007; Nestvold et al, 2008; Zhou et al, 2008; Zhu et al, 2011; Zinöcker et al, 2011a;Lin et al, 2012). Furthermore, rat models have been employed to test prevention or treatment of GvHD by therapeutic regimens involving immunomodulatory drugs (Tutschka et al, 1979; Vogelsang et al, 1986; Vogelsang et al, 1988; Mrowka et al, 1994; Ohajekwe et al, 1995; Pakkala et al, 2001; Okayama et al, 2006; Wolff et al, 2006; Jäger et al, 2007), infusion or induction of various suppressive cell types (Itakura et al, 2007; Aksu et al, 2008; Nestvold et al, 2008; Kitazawa et al, 2010; Zinöcker et al, 2011b; Kitazawa et al, 2012; Zinöcker et al, 2012), UV irradiation (Ohajekwe et al, 1995; Gowing et al, 1998), serum transfusion (Shimizu et al, 1997), surgical techniques (Kobayashi et al, 1998), and prolonged distribution of a chemical agent with subcutaneously implanted osmotic pumps (Fidler et al, 1993). …”

Section: Hematopoietic Cell Transplantation In Humans and Animalsmentioning

confidence: 99%

Immune Reconstitution and Graft-Versus-Host Reactions in Rat Models of Allogeneic Hematopoietic Cell Transplantation

Zinöcker¹,

Dressel²,

Wang³

et al. 2012

Front. Immun.

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Allogeneic hematopoietic cell transplantation (alloHCT) extends the lives of thousands of patients who would otherwise succumb to hematopoietic malignancies such as leukemias and lymphomas, aplastic anemia, and disorders of the immune system. In alloHCT, different immune cell types mediate beneficial graft-versus-tumor (GvT) effects, regulate detrimental graft-versus-host disease (GvHD), and are required for protection against infections. Today, the “good” (GvT effector cells and memory cells conferring protection) cannot be easily separated from the “bad” (GvHD-causing cells), and alloHCT remains a hazardous medical modality. The transplantation of hematopoietic stem cells into an immunosuppressed patient creates a delicate environment for the reconstitution of donor blood and immune cells in co-existence with host cells. Immunological reconstitution determines to a large extent the immune status of the allo-transplanted host against infections and the recurrence of cancer, and is critical for long-term protection and survival after clinical alloHCT. Animal models continue to be extremely valuable experimental tools that widen our understanding of, for example, the dynamics of post-transplant hematopoiesis and the complexity of immune reconstitution with multiple ways of interaction between host and donor cells. In this review, we discuss the rat as an experimental model of HCT between allogeneic individuals. We summarize our findings on lymphocyte reconstitution in transplanted rats and illustrate the disease pathology of this particular model. We also introduce the rat skin explant assay, a feasible alternative to in vivo transplantation studies. The skin explant assay can be used to elucidate the biology of graft-versus-host reactions, which are known to have a major impact on immune reconstitution, and to perform genome-wide gene expression studies using controlled combinations of minor and major histocompatibility between the donor and the recipient.

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Section: Hematopoietic Cell Transplantation In Humans and Animalsmentioning

confidence: 99%

Immune Reconstitution and Graft-Versus-Host Reactions in Rat Models of Allogeneic Hematopoietic Cell Transplantation

Zinöcker¹,

Dressel²,

Wang³

et al. 2012

Front. Immun.

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“…Cyclophosphamide has been used in the past along with bone marrow transplantation and achieved stable mixed chimerism without graft‐versus‐host disease . However, regardless of increased myeloid chimerism in the ASC‐CYP group, the allograft acceptance rate did not improve after single cyclophosphamide administration compared to the ASC group, which might relate to insufficient myelodepletion at 50 mg per kg body weight; indeed, in the ASC‐CYP group, WBC counts recovered faster than in the ASC‐ALS group.…”

Section: Discussionmentioning

confidence: 93%

“…While some authors suggest stable chimerism is a prerequisite for achievement of tolerance, others report long‐term allograft tolerance with initial, transient chimerism in the early posttransplant phase . Regardless of the robustness or longevity of donor chimerism, a uniform requirement seems to be induction regimens comprising myeloablative or cyto‐depletional strategies in the recipient to generate a permissive immune window for engraftment of donor cells …”

Section: Introductionmentioning

confidence: 99%

Adipose-derived stromal cell therapy combined with a short course nonmyeloablative conditioning promotes long-term graft tolerance in vascularized composite allotransplantation

Schweizer

Taddeo

Waldner

et al. 2020

American Journal of Transplantation

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The risks of chronic immunosuppression limit the utility of vascularized composite allotransplantation (VCA) as a reconstructive option in complex tissue defects. We evaluated a novel, clinically translatable, radiation-free conditioning protocol that combines anti-lymphocyte serum (ALS), tacrolimus, and cytotoxic T-lymphocyteassociated protein 4 immunoglobulin (CTLA4-Ig) with adipose-derived stromal cells (ASCs) to allow VCA survival without long-term systemic immunosuppression. Fullmismatched rat hind-limb-transplant recipients received tacrolimus (0.5 mg/kg) for 14 days and were assigned to 4 groups: controls (CTRL) received no conditioning;ASC-group received CTLA4-Ig (10 mg/kg body weight i.p. postoperative day [POD] 2, 4, 7) and donor ASCs (1 × 10 6 iv, POD 2, 4, 7, 15, 28); the ASC-cyclophosphamide (CYP)-group received CTLA4-Ig, ASC plus cyclophosphamide (50 mg/kg ip, POD 3); the ASC-ALS-group received CTLA4-Ig, ASCs plus ALS (500 µL ip, POD 1, 5). Banff grade III or 120 days were endpoints. ASCs suppressed alloresponse in vitro. Median rejection-free VCA survival was 28 days in CTRL (n = 7), 34 in ASC (n = 6), and 27.5 in ASC-CYP (n = 4). In contrast, ASC-ALS achieved significantly longer, rejection-free VCA survival in 6/7 animals (86%), with persistent mixed donor-cell chimerism, and elevated systemic and allograft skin T regs , with no signs of acute cellular rejection.Taken together, a regimen comprised of short-course tacrolimus, repeated CTLA4-Ig and ASC administration, combined with ALS, promotes long-term VCA survival without chronic immunosuppression. K E Y W O R D S basic (laboratory) research/science, cellular transplantation (nonislet), cytokines/cytokine receptors, immunosuppressant -fusion proteins and monoclonal antibodies: belatacept, immunosuppression/immune modulation, immunosuppressive regimens, stem cells, tolerance: costimulation blockade, translational research/science, vascularized composite and reconstructive transplantation | 1273 SCHWEIZER Et al. S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Schweizer R, Taddeo A, Waldner M, et al. Adipose-derived stromal cell therapy combined with a short course nonmyeloablative conditioning promotes long-term graft tolerance in vascularized composite allotransplantation. Am J Transplant. 2020;20:1272-1284.

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Efficacy of Transient Treatment with FK506 in the Early Phase on Cyclophosphamide-Induced Bone Marrow Chimerism and Transplant Tolerance across MHC Barriers

Cited by 2 publications

References 30 publications

Immune Reconstitution and Graft-Versus-Host Reactions in Rat Models of Allogeneic Hematopoietic Cell Transplantation

Immune Reconstitution and Graft-Versus-Host Reactions in Rat Models of Allogeneic Hematopoietic Cell Transplantation

Adipose-derived stromal cell therapy combined with a short course nonmyeloablative conditioning promotes long-term graft tolerance in vascularized composite allotransplantation

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