scholarly journals Polyclonal Recipient nTregs Are Superior to Donor or Third-Party Tregs in the Induction of Transplantation Tolerance

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Nina Pilat ◽  
Christoph Klaus ◽  
Karin Hock ◽  
Ulrike Baranyi ◽  
Lukas Unger ◽  
...  
Keyword(s):  
Clinical Setting ◽  
Large Scale ◽  
T Regulatory Cells ◽  
Third Party ◽  
Mixed Chimerism ◽  
Effector Cells ◽  
Treg Population ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Induction of donor-specific tolerance is still considered as the “Holy Grail” in transplantation medicine. The mixed chimerism approach is virtually the only tolerance approach that was successfully translated into the clinical setting. We have previously reported successful induction of chimerism and tolerance using cell therapy with recipient T regulatory cells (Tregs) to avoid cytotoxic recipient treatment. Treg therapy is limited by the availability of cells as large-scale expansion is time-consuming and associated with the risk of contamination with effector cells. Using a costimulation-blockade based bone marrow (BM) transplantation (BMT) model with Treg therapy instead of cytoreductive recipient treatment we aimed to determine the most potent Treg population for clinical translation. Here we show that CD4+CD25+in vitroactivated nTregs are superior to TGFβinduced iTregs in promoting the induction of chimerism and tolerance. Therapy with nTregs (but not iTregs) led to multilineage chimerism and donor-specific tolerance in mice receiving as few as 0.5×106cells. Moreover, we show that only recipient Tregs, but not donor or third-party Tregs, had a beneficial effect on BM engraftment at the tested doses. Thus, recipient-type nTregs significantly improve chimerism and tolerance and might be the most potent Treg population for translation into the clinical setting.

scholarly journals Characterization of mixed allogeneic chimeras. Immunocompetence, in vitro reactivity, and genetic specificity of tolerance.

1985 ◽  
Vol 162 (1) ◽  
pp. 231-244 ◽  
Author(s):  
S T Ildstad ◽  
S M Wren ◽  
J A Bluestone ◽  
S A Barbieri ◽  
D H Sachs
Keyword(s):  
Third Party ◽  
Mixed Chimerism ◽  
Skin Grafts ◽  
Cell Responses ◽  
Skin Allografts ◽  
Conventional Animal ◽  
Specific Tolerance

Mixed allogeneically reconstituted mice (B10 + B10.D2----B10) that specifically accept B10.D2 tail skin allografts were examined for in vivo and in vitro immunocompetence, patterns of hematopoietic repopulation, and in vitro reactivity. In vitro, mixed allogeneic chimeras (B10 + B10.D2----B10) manifested specific tolerance in mixed lymphocyte reactions and cell-mediated lympholysis to B10 and B10.D2 splenocytes, with normal responses to third-party (B10.BR) cells. Such chimeras were immunocompetent in B cell and helper T cell responses, as assessed by their primary plaque forming cell responses to in vivo sheep red blood cell immunization. This is in contrast to fully allogeneic chimeras, which responded less well. In addition, survival of the mixed allogeneic chimeras in a conventional animal facility was superior to that of fully allogeneic chimeras, and similar to syngeneically reconstituted (B10----B10) mice. Specific tolerance to skin grafts, degree of allogeneic engraftment, and persistence of chimerism was also assessed in a noncongenic mixed allogeneic combination (B10 + C3H----B10). Such animals manifested specific hyporeactivity to C3H skin allografts, but eventual chronic rejection of the grafts occurred in spite of stable and persistent mixed chimerism. MHC-congenic (B10.BR) skin grafts were accepted indefinitely in the same animals, suggesting that skin-specific non-major histocompatibility complex antigens were responsible for rejection of the C3H skin allografts.

scholarly journals In situ recruitment of regulatory T cells promotes donor-specific tolerance in vascularized composite allotransplantation

2020 ◽  
Vol 6 (11) ◽  
pp. eaax8429 ◽  
Author(s):  
James D. Fisher ◽  
Wensheng Zhang ◽  
Stephen C. Balmert ◽  
Ali M. Aral ◽  
Abhinav P. Acharya ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Tolerance ◽  
Immunosuppressive Drugs ◽  
Vascularized Composite Allotransplantation ◽  
Local Enrichment ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Vascularized composite allotransplantation (VCA) encompasses face and limb transplantation, but as with organ transplantation, it requires lifelong regimens of immunosuppressive drugs to prevent rejection. To achieve donor-specific immune tolerance and reduce the need for systemic immunosuppression, we developed a synthetic drug delivery system that mimics a strategy our bodies naturally use to recruit regulatory T cells (Treg) to suppress inflammation. Specifically, a microparticle-based system engineered to release the Treg-recruiting chemokine CCL22 was used in a rodent hindlimb VCA model. These “Recruitment-MP” prolonged hindlimb allograft survival indefinitely (>200 days) and promoted donor-specific tolerance. Recruitment-MP treatment enriched Treg populations in allograft skin and draining lymph nodes and enhanced Treg function without affecting the proliferative capacity of conventional T cells. With implications for clinical translation, synthetic human CCL22 induced preferential migration of human Treg in vitro. Collectively, these results suggest that Recruitment-MP promote donor-specific immune tolerance via local enrichment of suppressive Treg.

SUMMARY OF A PHASE II PROTOCOL TO ATTEMPT TO INDUCE MIXED CHIMERISM AND DONOR-SPECIFIC TOLERANCE TO RENAL AND CARDIAC ALLOGRAFTS.

2000 ◽  
Vol 69 (Supplement) ◽  
pp. S294-S295
Author(s):  
Suzanne T. Ildstad ◽  
Roger Herzig ◽  
Christina Kaufman ◽  
Pamela Crilley ◽  
Susan Brozena ◽  
...  
Keyword(s):  
Phase Ii ◽  
Mixed Chimerism ◽  
Cardiac Allografts ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

NK Cells Efficiently Prevent Engraftment of Donor Stem Cells after Tolerigenic Bone Marrow Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3025-3025 ◽  
Author(s):  
Leslie Kean ◽  
Kelly Hamby ◽  
Thomas Pearson ◽  
Christian Larsen
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
T Cell ◽  
Nk Cells ◽  
Mixed Chimerism ◽  
Low Doses ◽  
Donor Bone Marrow ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Abstract Introduction: Immunologic tolerance remains an elusive goal of transplantation. In mice, mixed-chimerism and donor-specific tolerance can be induced by blocking the CD28/CD40L T-cell costimulatory pathways after bone marrow transplant (BMT). However, large doses of marrow (~1x109 cells/kg) are required, and these regimens have not yet been successfully translated to clinical practice. There is a growing body of evidence that NK cells may play a central role in the failure of low doses of donor bone marrow to engraft, but the mechanisms underlying NK alloreactivity remain to be determined. Methods: (1) BMT in the presence of CD28/CD40L T cell costimulation blockade was performed using C57BL/6 (B6) recipients and Balb/C donor bone marrow. The role of host-anti-donor NK alloreactivity in preventing engraftment was determined by specifically depleting B6 NK cells. The contribution of the NK cell-surface receptor, LFA1 to NK alloreactivity was determined with the anti-LFA1 blocking antibody M17/5.2. (2) An in vivo NK alloreactivity assay was developed that should allow the investigation of the mechanism of NK alloreactivity and the molecular mediators of this process. In this assay, CFSE-labeled B6 splenocytes were adoptively transferred into B6xBalbC F1 progeny. As such, alloreactivity was specifically mediated by NK cells. NK alloreactivity was measured flow-cytometrically by the disappearance of the CFSE-labeled B6 population. Results: Transient depletion of recipient NK cells resulted in increased donor stem cell survival and the induction of stable mixed-chimerism and tolerance despite BMT with low doses (≤2x106 cells) of donor bone marrow. This effect was specific to allogeneic donor cells: depletion of NK cells did not increase engraftment of syngeneic bone marrow. Blocking the adhesion molecule, LFA-1 recapitulated the effects of whole-scale NK depletion. Newly emergent NK cells exhibited significantly lower expression of the donor-specific activating receptor, Ly49D, and these NK cells did not exhibit in vivo alloreactivity. These results suggest that the NK repertoire in the mixed-chimeric setting exhibited donor-specific tolerance. Using the in vivo hybrid resistance NK alloreactivity assay, we measured 80% NK-specific target killing 8 days after adoptive transfer. Significantly less killing occurred at 2, 4, and 6 days. Pre-sensitizing the recipient for 4 days increased the efficiency of killing—from 50% to 80%, suggesting a potent activation phenomenon required for efficient NK allorecognition and/or cytotoxicity. Implications: These results reveal the importance of NK alloreactivity in the acquisition of mixed-chimerism after BMT at limiting stem cell doses, and suggest that clinical approaches to tolerance-induction transplantation may require mechanisms to control NK alloreactivity.

MODIFICATIONS OF THE CONDITIONING REGIMEN FOR ACHIEVING MIXED CHIMERISM AND DONOR-SPECIFIC TOLERANCE IN CYNOMOLGUS MONKEYS1

1997 ◽  
Vol 64 (5) ◽  
pp. 709-716 ◽  
Author(s):  
Masaaki Kimikawa ◽  
David H. Sachs ◽  
Robert B. Colvin ◽  
Amelia Bartholomew ◽  
Tatsuo Kawai ◽  
...  
Keyword(s):  
Conditioning Regimen ◽  
Mixed Chimerism ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

STABLE MIXED CHIMERISM AND DONOR SPECIFIC TOLERANCE WITHOUT WHOLE BODY IRRADIATION IN A LARGE ANIMAL MODEL

1999 ◽  
Vol 67 (7) ◽  
pp. S34
Author(s):  
Y. Fuchimoto ◽  
C. Huang ◽  
Q. Chang ◽  
K. Yamada ◽  
D. Neville ◽  
...  
Keyword(s):  
Animal Model ◽  
Whole Body ◽  
Large Animal Model ◽  
Mixed Chimerism ◽  
Large Animal ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

scholarly journals CD28-B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2.

1995 ◽  
Vol 181 (5) ◽  
pp. 1869-1874 ◽  
Author(s):  
M H Sayegh ◽  
E Akalin ◽  
W W Hancock ◽  
M E Russell ◽  
C B Carpenter ◽  
...  
Keyword(s):  
Graft Rejection ◽  
Tissue Injury ◽  
Treated Group ◽  
Third Party ◽  
Prolonged Survival ◽  
Cardiac Allografts ◽  
Mononuclear Cell Infiltrates ◽  
Donor Specific Tolerance

Blocking the CD28-B7 T cell costimulatory pathway with the fusion protein CTLA4Ig inhibits alloimmune responses in vitro and in vivo and induces tolerance to cardiac allografts in mice and rats, but the mechanisms mediating the tolerant state in vivo are unknown. Here, we report the effects and potential mechanisms of CTLA4Ig in the rat renal allograft model. LEW rats were nephrectomized and received renal allografts from major histocompatibility complex-incompatible WF rats. While all untreated and control immunoglobulin (Ig)-treated animals acutely rejected their allografts and died, 86% of rats that received a single injection of CTLA4Ig on day 2 after transplantation had prolonged survival (> 60-100 days) with preserved renal function. By contrast, only 29% of animals that received CTLA4Ig on the day of engraftment had prolonged survival. Long-term survivors (> 100 days) exhibited donor-specific tolerance, accepting donor-matched WF but acutely rejecting third-party BN cardiac allografts. Immunohistological analysis of grafts sampled at 1 week after transplantation showed that both control and CTLA4Ig-treated animals had mononuclear cell infiltrates, with a higher percentage of CD4+ cells in the CTLA4Ig-treated group. However, while this was associated with vasculitis and tubulitis in control grafts, there was no evidence of tissue injury in CTLA4Ig-treated animals. The immune response leading to graft rejection in control animals was characterized by expression of the T helper (Th) type 1 cytokines interleukin (IL)-2 and interferon-gamma. In contrast, the persistent CD4+ infiltrate without graft rejection in CTLA4Ig-treated animals was associated with increased staining for the Th2-related cytokines IL-4 and IL-10. Furthermore, grafts from CTLA4Ig-treated animals had marked upregulation of intragraft staining for IgG1, but not IgG2a or IgG2b. Administration of rIL-2 to CTLA4Ig-treated animals restored allograft rejection in 50% of animals tested. These results confirm that blockade of the CD28-B7 pathway after alloantigenic challenge induces donor-specific acceptance of vascularized organ allografts, and indicates in this model that CTLA4Ig inhibits Th1 but spares Th2 cytokines in vivo.

scholarly journals Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen.

1989 ◽  
Vol 169 (2) ◽  
pp. 493-502 ◽  
Author(s):  
Y Sharabi ◽  
D H Sachs
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Host Resistance ◽  
Marrow Transplantation ◽  
Whole Body ◽  
Mixed Chimerism ◽  
Skin Grafts ◽  
Preparative Regimen ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

The use of allogeneic bone marrow transplantation as a means of inducing donor-specific tolerance across MHC barriers could provide an immunologically specific conditioning regimen for organ transplantation. However, a major limitation to this approach is the toxicity of whole body irradiation as currently used to abrogate host resistance and permit marrow engraftment. The present study describes methodology for abrogating host resistance and permitting marrow engraftment without lethal irradiation. Our preparative protocol involves administration of anti-CD4 and anti-CD8 mAbs in vivo, 300-rad WBI, 700-rad thymic irradiation, and unmanipulated fully MHC-disparate bone marrow. B10 mice prepared by this regimen developed stable mixed lymphohematopoetic chimerism without any clinical evidence of graft-vs.-host disease. Engraftment was accompanied by induction of specific tolerance to donor skin grafts (B10.D2), while third-party skin grafts (B10.BR) were promptly rejected. Mice treated with the complete regimen without bone marrow transplantation appeared healthy and enjoyed long-term survival. This study therefore demonstrates that stable mixed chimerism with donor-specific tolerance can be induced across an MHC barrier after a nonlethal preparative regimen, without clinical GVHD and without the risk of aplasia.

Mixed chimerism induces donor-specific T-cell tolerance across a highly disparate xenogeneic barrier

Blood ◽  
2002 ◽  
Vol 99 (10) ◽  
pp. 3823-3829 ◽  
Author(s):  
Masahiro Abe ◽  
Jin Qi ◽  
Megan Sykes ◽  
Yong-Guang Yang
Keyword(s):  
Immune Responses ◽  
Mixed Chimerism ◽  
Igg Antibody ◽  
Xenograft Rejection ◽  
Donor Skin ◽  
Hematopoietic Chimerism ◽  
Clinical Potential ◽  
Donor Specific Tolerance ◽  
First Time ◽  
Specific Tolerance

Induction of tolerance is likely to be essential for successful xenotransplantation because immune responses across xenogeneic barriers are vigorous. Although mixed hematopoietic chimerism leads to stable donor-specific tolerance in allogeneic and closely related xenogeneic (eg, rat-to-mouse) combinations, the ability of this approach to induce tolerance across a highly disparate xenogeneic barrier has not yet been demonstrated. In this study, we investigated the immune responses of murine T cells that developed in mice with pre-established porcine hematopoietic chimerism. Our results show for the first time that induction of porcine hematopoietic chimerism can eliminate the development of antiporcine donor responses in a highly disparate xenogeneic species. Porcine hematopoietic chimeras showed donor-specific nonresponsiveness in the mixed lymphocyte reaction, lack of antidonor IgG antibody production, and acceptance of donor skin grafts. Thus, mixed chimerism is capable of inducing tolerance in a highly disparate xenogeneic combination and may have clinical potential to prevent xenograft rejection.

Sign in / Sign up

Export Citation Format

Share Document