Tolerance--Is It Worth It?

Finger, Erik B.; Strom, Terry B.; Matas, Arthur J.

doi:10.1101/cshperspect.a015594

Cited by 5 publications

(4 citation statements)

References 133 publications

(124 reference statements)

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“…In this model, mouse lung allografts remain free of rejection without the need for maintenance immunosuppression and recipients accept donor‐matched heart grafts. Successful tolerance induction in the clinics, for example through mixed chimerism or adoptive transfer of regulatory T cells, would be desirable to avoid adverse effects of immunosuppressive drugs, such as pharmacological toxicity as well as an increased risk for opportunistic infections and malignancies 11 . We now show that administration of Pam 3 Cys 4 , a bacterial lipopeptide, into the donor airway before implantation abrogates tolerance induction.…”

Section: Introductionmentioning

confidence: 73%

Bacterial products in donor airways prevent the induction of lung transplant tolerance

Tanaka

Gauthier

Terada

et al. 2021

American Journal of Transplantation

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Lung transplantation is the only established lifesaving option for many patients suffering from end-stage pulmonary disease. The selection of appropriate lung donors is a critical element of the transplant process. Infiltrates on chest imaging studies and the presence of bacteria in the donor airways have long been considered contraindications to the use of lungs for transplantation. 1 Because of a scarcity in suitable lungs for transplantation and a rising waitlist mortality rate, strategies have been increasingly employed to expand the donor pool. To this end, one such approach is the use of extended criteria lung donors, which may harbor infections. The use of donor lungs with bacterial colonization or pneumonia, however, is controversial. Whereas some

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Section: Introductionmentioning

confidence: 73%

Bacterial products in donor airways prevent the induction of lung transplant tolerance

Tanaka

Gauthier

Terada

et al. 2021

American Journal of Transplantation

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“…Immunosuppression increases the susceptibility to infections and cancers, while under‐immunosuppression may provoke episodes of rejection. In a substantial fraction of transplant recipients late graft loss cannot be prevented by current means, which further increases the demand for donor organs, which are a scarce and limited resource . Therefore, transplant immunologists still crave for a state where the recipient immune system accepts donor antigens specifically and permanently while remaining otherwise fully immunologically competent.…”

Section: Still In Search Of the Holy Grailmentioning

confidence: 99%

Murine models of transplantation tolerance through mixed chimerism: advances and roadblocks

Mahr

Wekerle

2017

Clinical and Experimental Immunology

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Organ transplantation is the treatment of choice for patients with end-stage organ failure, but chronic immunosuppression is taking its toll in terms of morbidity and poor efficacy in preventing late graft loss. Therefore, a drugfree state would be desirable where the recipient permanently accepts a donor organ while remaining otherwise fully immunologically competent. Mouse studies unveiled mixed chimerism as an effective approach to induce such donor-specific tolerance deliberately and laid the foundation for a series of clinical pilot trials. Nevertheless, its widespread clinical implementation is currently prevented by cytotoxic conditioning and limited efficacy. Therefore, the use of mouse studies remains an indispensable tool for the development of novel concepts with potential for translation and for the delineation of underlying tolerance mechanisms. Recent innovations developed in mice include the use of pro-apoptotic drugs or regulatory T cell (T reg ) transfer for promoting bone marrow engraftment in the absence of myelosuppression and new insight gained in the role of innate immunity and the interplay between deletion and regulation in maintaining tolerance in chimeras. Here, we review these and other recent advances in murine studies inducing transplantation tolerance through mixed chimerism and discuss both the advances and roadblocks of this approach.

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“…3,4 Donor-specific immunological tolerance could not only improve graft and patient survival but also the quality of life because it would make the use of immunosuppressive drugs obsolete. 5,6 A promising tolerance approach is the cotransplantation of donor bone marrow (BM) together with the solid organ graft, inducing hematopoietic chimerism. First observations of tolerance associated with the transfer of hematopoietic stem cells (HSCs) were already made by Owen in 1945 and Billingham et al in 1952, who noted chimerism and subsequent tolerance in the offspring of freemartin cattle because of a shared placental circulation.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Combining Treg Therapy With Donor Bone Marrow Transplantation: Experimental Progress and Clinical Perspective

Weijler,

Wekerle

2023

Transplantation

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Donor-specific tolerance remains a goal in transplantation because it could improve graft survival and reduce morbidity. Cotransplantation of donor hematopoietic cells to achieve chimerism is a promising approach for tolerance induction, which was successfully tested in clinical trials. However, current protocols are associated with side effects related to the myelosuppressive recipient conditioning, which makes it difficult to introduce them as standard therapy. More recently, adoptive cell therapy with polyclonal or donor-specific regulatory T cells (Treg) proved safe and feasible in several transplant trials, but it is unclear whether it can induce tolerance on its own. The combination of both approaches—Treg therapy and hematopoietic cell transplantation—leads to chimerism and tolerance without myelosuppressive treatment in murine models. Treg therapy promotes engraftment of allogeneic hematopoietic cells, reducing conditioning requirements and enhancing regulatory mechanisms maintaining tolerance. This review discusses possible modes of action of transferred Treg in experimental chimerism models and describes translational efforts investigating the potent synergy of Treg and chimerism.

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Tolerance--Is It Worth It?

Cited by 5 publications

References 133 publications

Bacterial products in donor airways prevent the induction of lung transplant tolerance

Bacterial products in donor airways prevent the induction of lung transplant tolerance

Murine models of transplantation tolerance through mixed chimerism: advances and roadblocks

Combining Treg Therapy With Donor Bone Marrow Transplantation: Experimental Progress and Clinical Perspective

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