Ex Vivo-Expanded Natural CD4+CD25+ Regulatory T Cells Synergize With Host T-Cell Depletion to Promote Long-Term Survival of Allografts

Xia, Guliang; He, Jie; Leventhal, Joseph R.

doi:10.1111/j.1600-6143.2007.02088.x

Cited by 87 publications

(75 citation statements)

References 50 publications

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“…Cell ablation around the time of transplantation is thought to debulk alloreactive T cells, which are present at high frequencies (23,24), inducing a favorable ratio of regulatory cells to effector cells. Increasing understanding of Treg biology has resulted in cell therapy using allogeneic transplantation of ex vivo expanded CD4 ϩ CD25 ϩ Tregs in animal models, and this strategy now is being tested clinically (25).…”

Section: Discussionmentioning

confidence: 99%

ECDI-fixed allogeneic splenocytes induce donor-specific tolerance for long-term survival of islet transplants via two distinct mechanisms

Luo

Pothoven

McCarthy

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

158

233

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A major challenge for human allogeneic islet transplantation is the development of effective methods to induce donor-specific tolerance to obviate the need for life-long immunosuppression that is toxic to the insulin-producing ␤ cells and detrimental to the host. We developed an efficient donor-specific tolerance therapy that utilizes infusions of ethylene carbodiimide (ECDI)-treated donor splenic antigen-presenting cells that results in indefinite survival of allogeneic islet grafts in the absence of immunosuppression. Furthermore, we show that induction of tolerance is critically dependent on synergistic effects between an intact programmed death 1 receptorprogrammed death ligand 1 signaling pathway and CD4 ؉ CD25 ؉ Foxp3 ؉ regulatory T cells. This highly efficient antigen-specific therapy with a complete avoidance of immunosuppression has significant therapeutic potential in human islet cell transplantation.anergy ͉ programmed death-1 ͉ regulatory T cells ͉ transplantation ͉ islet transplantation

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Section: Discussionmentioning

confidence: 99%

ECDI-fixed allogeneic splenocytes induce donor-specific tolerance for long-term survival of islet transplants via two distinct mechanisms

Luo

Pothoven

McCarthy

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

158

233

View full text Add to dashboard Cite

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“…These in vitro generated T-regs could induce tolerance and already has been used in some trials. [47][48] (2) In vivo generated T-regs could induce tolerance. The most actively investigated tolerance induction regimen is pretreatment of the patient using donor-specific transfusion with/without prepurified T-regs, and then examining the patient's administration with blocking monoclonal antibodies targeting CD4, CD154 (CD40L), lymphocyte function associated antigen-1, and ICAM-1 costimulation.…”

Section: Types: Adoptive Transfer Of Ex Vivo Expanded T-regs and De mentioning

confidence: 99%

Regulatory T Cells as a Therapeutic Tool To Induce Solid-Organ Transplant Tolerance: Current Clinical Experiences

Nikoueinejad¹,

Sharif²,

Amirzargar³

et al. 2013

Exp Clin Transplant

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Long-term tolerance is potentially an ideal in organ transplant. Achieving this leads us to eliminate immunosuppressive therapies and their associated side effects. Although most succession in this field belongs to mixed chimerism methods of tolerance induction, regulatory T cells and (T-reg)-based methods also have been demonstrated to prevent organ rejection and lead to transplant tolerance through different mechanisms. In contrast to chimeric protocols (which require bone marrow transplant), T-reg-mediated protocols do not aggressively manipulate blood and the immune system. Most treatment has been done for graft-versus-host disease after hematopoietic stem cell transplant. This review describes different types and mechanisms of action and clinical strategies using T-regs to induce transplant tolerance.

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“…In fact, although T regulatory cells associated with transplantation tolerance (24,30,31,43) are induced by Thymoglobulin and mATG (23,25,26,32,33) and are responsible for mATGmediated prolonged graft survival (16), we did not see increases in T regulatory cells with the mATG and methotrexate combination over that of mATG alone. In addition, there was no evidence of enhanced depletion of T cells, and only a modest extension of mATG effects was observed as a result of blockade of anti-drug Ab responses by methotrexate.…”

Section: Discussionmentioning

confidence: 71%

“…In particular, as T regulatory cells have been associated with longterm graft survival in transplantation (23,24,30,31), are induced by Thymoglobulin and mATG (22,25,26,32,33), and have previously been demonstrated to be responsible for delayed graft rejection following mATG (16), CD3 + Foxp3 + cells, which bear a phenotype consistent with regulatory T cells, were evaluated. To assess histologic changes in long-surviving grafts, cardiac grafts were collected from the mATG and methotrexate combinationtreated group and the untreated syngeneic group at least 100 d after transplantation.…”

Section: Matg and Methotrexate Cotreatment Reduces Allograft Rejectiomentioning

confidence: 99%

Transient Low-Dose Methotrexate Induces Tolerance to Murine Anti-Thymocyte Globulin and Together They Promote Long-Term Allograft Survival

Joseph¹,

Neff²,

Richard³

et al. 2012

The Journal of Immunology

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Rabbit anti-thymocyte globulin (Thymoglobulin) effectively treats transplant rejection but induces anti-rabbit Ab responses, which limits routine readministration. Aiming to tolerize anti-rabbit responses, we coadministered a brief methotrexate regimen with a murine version of Thymoglobulin (mATG) for effects on anti-mATG Abs and cardiac allotransplantation in mice. Although both single and three courses of methotrexate could significantly inhibit anti-drug Ab titers to repeated mATG treatment, surprisingly, the single course given at the first mATG administration was most effective (>99% reduction). The transient methotrexate treatment also significantly improved pharmacokinetics and pharmacodynamics of repeated mATG administration. In the cardiac allograft model, the combination of transient mATG and methotrexate given only at the time of transplant dramatically improved allograft survival (>100 d) over either agent alone (<30 d). Anti-drug Ab titers were reduced and mATG exposure was increased which resulted in prolonged rather than enhanced mATG-mediated effects when combined with methotrexate. Moreover, methotrexate administration significantly reduced alloantibodies, suggesting that methotrexate not only decreases anti-drug Ab responses but also reduces Ab responses to multiple tissue-derived alloantigens simultaneously. These data suggest that mATG and methotrexate together can provide long-term allograft survival potentially through the induction of immune tolerance.

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Ex Vivo-Expanded Natural CD4+CD25+ Regulatory T Cells Synergize With Host T-Cell Depletion to Promote Long-Term Survival of Allografts

Cited by 87 publications

References 50 publications

ECDI-fixed allogeneic splenocytes induce donor-specific tolerance for long-term survival of islet transplants via two distinct mechanisms

ECDI-fixed allogeneic splenocytes induce donor-specific tolerance for long-term survival of islet transplants via two distinct mechanisms

Regulatory T Cells as a Therapeutic Tool To Induce Solid-Organ Transplant Tolerance: Current Clinical Experiences

Transient Low-Dose Methotrexate Induces Tolerance to Murine Anti-Thymocyte Globulin and Together They Promote Long-Term Allograft Survival

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