TOLERANCE INDUCTION IN a FULLY ALLOGENEIC COMBINATION USING ANTI-T CELL RECEPTOR-αβ MONOCLONAL ANTIBODY, LOW DOSE IRRADIATION, AND DONOR BONE MARROW TRANSFUSION

Nomoto, Ken’ichi; YUNG-YUN, KONG; Omoto, Kazuya; Umesue, Masayoshi; Murakami, Yoshiyuki; MATSUZAKI, GORO; Nomoto, Kikuo

doi:10.1097/00007890-199502150-00015

Cited by 29 publications

(11 citation statements)

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“…The induction of mixed chimerism reliably leads to a robust state of tolerance that provides a promising approach to donor‐specific tolerance induction 11–17 . Costimulatory blockade agents are readily tolerated by the host, obviating the use of pretransplant conditioning with irradiation and/or cytotoxic drugs that is common in most established regimens.…”

Section: Discussionmentioning

confidence: 99%

“…The establishment of mixed haematopoietic chimerism is associated with specific immunological tolerance, and the results from various rodent models demonstrate the potential application of mixed chimerism regimens to promote transplantation tolerance 11–15 . Nevertheless, most regimens require host conditioning with irradiation and/or depletion of peripheral immunity, making them prohibitive owing to potential toxicity and the risk of graft‐versus‐host disease (GVHD).…”

Section: Introductionmentioning

confidence: 99%

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Simultaneous administration of a low‐dose mixture of donor bone marrow cells and splenocytes plus adenovirus containing the CTLA4Ig gene result in stable mixed chimerism and long‐term survival of cardiac allograft in rats

et al. 2003

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SUMMARYT-cell costimulatory blockade combined with donor bone marrow transfusion may induce mixed chimerism, rendering robust tolerance in transplanted organs and cells. However, most protocols entail high doses of donor bone marrow cells (BMCs) or repeated administration of costly agents that block costimulatory pathways, thus delaying clinical development. To circumvent these shortcomings, we developed a strategy in which the dosage of donor BMCs was reduced but compensated by donor splenocytes (SPLCs). Furthermore, repeated administration of costly agents was replaced with a single injection of adenovirus expressing a gene of interest. In rat cardiac transplantation models, cardiac allografts from DA (RT-1 a ) rats were transplanted heterotopically into the abdomen of LEW (RT-1 1 ) recipient rats. Immediately after cardiac transplantation, an adenovirus vector (AdCTLA4Ig; 5 Â 10 9 plaqueforming units) containing the gene for CTLA4Ig was administered to recipients (n 6) simultaneously with a low dose of donor BMCs (1 Â 10 8 /rat) and SPLCs (5 Â 10 7 /rat) via the portal vein. The treated LEW recipient rats developed long-lasting mixed chimerism (>10% at >100 days) and exhibited long-term cardiac allografts (mean survival time of >200 days) compared with control recipients. Moreover, recipients displaying long-lasting mixed chimerism accepted subsequent donor skin allografts while promptly rejecting third-party skin allografts. These results suggest that blockade of the CD28-B7 pathway, using adenovirusmediated CTLA4Ig gene transfer, in concert with a low dosage of donor BMCs and SPLCs, may represent a feasible strategy to induce stable mixed chimerism and permit long-term survival of cardiac allografts.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Simultaneous administration of a low‐dose mixture of donor bone marrow cells and splenocytes plus adenovirus containing the CTLA4Ig gene result in stable mixed chimerism and long‐term survival of cardiac allograft in rats

et al. 2003

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“…Attempts have been made to develop T cell specific mAb reagents such as anti-TCRαβ in murine [59] and canine [60,61] HSC transplant models; however, no such reagents have yet been employed therapeutically in human trials. Rather, polyclonal antibody preparations such as anti-thymocyte globulin (ATG) and non-T cell specific monoclonal antibodies such as alemtuzumab, an antibody to CD52, which leads to depletion of T, B, NK, and some myeloid cells, are increasingly being used clinically to facilitate immunosuppression of allotransplant recipients, with conflicting results regarding benefit [62–64].…”

Section: Use Of Antibodies To Overcome Allogeneic Immune Barriersmentioning

confidence: 99%

The road to purified hematopoietic stem cell transplants is paved with antibodies

Logan

Shizuru

2012

Current Opinion in Immunology

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Hematopoietic progenitor cell replacement therapy remains a surprisingly unrefined process. In general, unmanipulated bone marrow or mobilized peripheral blood grafts which carry potentially harmful passenger cells are administered after treating recipients with high-dose chemo- and/or radiotherapy to eradicate malignant disease, eliminate immunologic barriers to allogeneic cell engraftment, and to “make space” for rare donor stem cells within the stem cell niche. The sequalae of such treatments are substantial, including direct organ toxicity and non-specific inflammation that contributes to the development of graft-versus-host disease and poor immune reconstitution. Passenger tumor cells that contaminate autologous hematopoietic grafts may contribute to relapse post-transplant. Use of antibodies to rid grafts of unwanted cell populations, and to eliminate or minimize the need for non-specifically cytotoxic therapies used to condition transplant recipients, will dramatically improve the safety profile of allogeneic and gene-modified autologous hematopoietic stem cell therapies.

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“…However, as the first regimens developed for the induction of mixed chimerism included ablation of the host hematopoietic compartment and peripheral T-cell repertoire using lethal total body irradiation (TBI), they had little clinical potential. Subsequently, nonmyeloablative protocols were developed, whereby the amount of host conditioning was minimized [11][12][13][14][15][16][17][18][19][20], often through the administration of T-cell-depleting antibodies or other lymphoablative measures, and by increasing the numbers of donor bone marrow cells (BMCs) administered.…”

mentioning

confidence: 99%

Tolerance in mixed chimerism – a role for regulatory cells?

Kurtz

Wekerle

Sykes

2004

Trends in Immunology

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TOLERANCE INDUCTION IN a FULLY ALLOGENEIC COMBINATION USING ANTI-T CELL RECEPTOR-αβ MONOCLONAL ANTIBODY, LOW DOSE IRRADIATION, AND DONOR BONE MARROW TRANSFUSION

Cited by 29 publications

References 0 publications

Simultaneous administration of a low‐dose mixture of donor bone marrow cells and splenocytes plus adenovirus containing the CTLA4Ig gene result in stable mixed chimerism and long‐term survival of cardiac allograft in rats

Simultaneous administration of a low‐dose mixture of donor bone marrow cells and splenocytes plus adenovirus containing the CTLA4Ig gene result in stable mixed chimerism and long‐term survival of cardiac allograft in rats

The road to purified hematopoietic stem cell transplants is paved with antibodies

Tolerance in mixed chimerism – a role for regulatory cells?

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