Transplantation Tolerance in Primates Following Total Lymphoid Irradiation and Allogeneic Bone Marrow Injection I. Orthotopic Liver Allografts

Myburgh, J. A.; Smit, J. A.; Hill, R.R.H.; Browde, S

doi:10.1097/00007890-198005000-00011

Cited by 27 publications

(6 citation statements)

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“…5 With this assumption, experimental efforts were renewed to give organ recipients the tolerance advantages of leukocyte chimerism while avoiding GVHD. This proved to be possible in selected cytoablation and cytoreduction models, [6][7][8] but only when donor cells made up Ն1% of the recipient blood leukocytes (macrochimerism). 9 Lower levels (microchimerism) had no effect.…”

Section: See Article On Page 1523mentioning

confidence: 99%

Tolerance for organ recipients: A clash of paradigms

Marcos¹,

Lakkis²,

Starzl³

2006

Liver Transpl

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Section: See Article On Page 1523mentioning

confidence: 99%

Tolerance for organ recipients: A clash of paradigms

Marcos¹,

Lakkis²,

Starzl³

2006

Liver Transpl

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“…Since Medawar and colleagues (1) reported the induction of specific transplantation tolerance in mice by neonatal injection of allogeneic bone marrow cells, the search for methods to induce specific tolerance in adult recipients has continued (2)(3)(4)(5). We have recently shown (6) that reconstitution of lethally irradiated B 10 mice with T cell-depleted syngeneic (B 10) plus xenogeneic (F344 rat) bone marrow results in long-term survival of animals without apparent graft vs. host or wasting disease and leads to specific prolongation of donor-type, fullthickness tail skin grafts.…”

mentioning

confidence: 99%

In vivo and in vitro characterization of specific hyporeactivity to skin xenografts in mixed xenogeneically reconstituted mice (B10 + F344 rat----B10).

Ildstad¹,

Wren²,

Sharrow³

et al. 1984

The Journal of Experimental Medicine

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Transplantation between genetically disparate individuals requires chemotherapeutic agents to suppress the rejection reaction. Although these agents are vital to the suppression of graft rejection, they have their own deleterious side effects caused by both nonspecific immunosuppression and drug toxicities. In addition, chronic rejection in varying degrees of severity often occurs despite the use of these agents.Since Medawar and colleagues (1) reported the induction of specific transplantation tolerance in mice by neonatal injection of allogeneic bone marrow cells, the search for methods to induce specific tolerance in adult recipients has continued (2-5). We have recently shown (6) that reconstitution of lethally irradiated B 10 mice with T cell-depleted syngeneic (B 10) plus xenogeneic (F344 rat) bone marrow results in long-term survival of animals without apparent graft vs. host or wasting disease and leads to specific prolongation of donor-type, fullthickness tail skin grafts. Such animals promptly rejected third party allogeneic and xenogeneic skin grafts with a time course similar to that of unirradiated control animals.Our hypothesis for explaining these preliminary results was that syngeneic components offered immunocompetence, while xenogeneic elements led to hyporeactivity across a species barrier. However, neither the extent or specificity of this phenomenon as assessed by in vivo and in vitro parameters nor the nature of T cell responsiveness had been characterized in these animals. In this paper, we present data detailing the extent and specificity of hyporeactivity achieved across a species barrier. Mixed reconstituted animals are shown to exhibit specific hyporeactivity to donor antigens as assessed by skin grafting and by in vitro assays, including mixed lymphocyte culture proliferative and cellular cytotoxicity. These animals were immunocompetent, as evidenced by rejection of third party mouse and rat skin grafts and development of anti-sheep red blood cell plaqueforming responses equivalent to those of syngeneic controls. This new approach offers a model for investigation of mechanisms of self-recognition and induction and maintenance of transplantation tolerance across species barriers.

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“…In deed, irradiation was the first successful method of im munosuppression used in clinical transplantation (18). There is limited information concerning experimental hematopoietic chimerism and induction of tolerance in large-animal models, and most experiments have used outbred animals (12,19). Experimental models generally use bone marrow and most involve irradiation.…”

Section: Induction Of Immunological Tolerance Through Irradimentioning

confidence: 99%

Induction of Allogeneic Islet Tolerance in a Large-Animal Model

et al. 2000

Cell Transplant

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For islet allotransplantation to become a therapy widely applicable to patients with insulin-dependent diabetes, it will be important to avoid conventional immunosuppression and yet maintain long-term rejection-free islet survival. This possibility was tested in a large-animal model using mixed allogeneic chimeras established using total lymphoid irradiation (TLI) and donor-specific bone marrow transplantation (BMTX). Four recipient sex-mismatched and DLA class II-matched English springer spaniels became chimeric after TLI and donor-specific BMTX. Subsequent donor-specific renal allografts survived for more than a year. Acceptance of a donor-specific skin graft and rejection of a third-party graft demonstrated tolerance with maintenance of immunocompetence. Pancreatic microfragments containing islets were refluxed into the splenic vein of the recipient. Purified islets were placed under the capsule of spleen and liver. After 75 days, recipients underwent total native pancreatectomy. All four chimeric pancreatectomized dogs had functioning islet grafts 75 days after transplantation, evidenced by a prompt rise in serum insulin levels following an IVGTT and histological demonstration of islet tissue at the site of transplantation. After removal of the transplanted islet tissue, no insulin was released after IVGTT. In summary, intrasplenic allogeneic canine islets transplanted into chimeric dogs rendered tolerant to donor MHC survive and function for greater than 75 days in the absence of immunosuppression. This study represents proof of the concept that allogeneic islet transplants have the potential to reverse diabetes without the use of conventional immunosuppression.

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Transplantation Tolerance in Primates Following Total Lymphoid Irradiation and Allogeneic Bone Marrow Injection I. Orthotopic Liver Allografts

Cited by 27 publications

References 0 publications

Tolerance for organ recipients: A clash of paradigms

Tolerance for organ recipients: A clash of paradigms

In vivo and in vitro characterization of specific hyporeactivity to skin xenografts in mixed xenogeneically reconstituted mice (B10 + F344 rat----B10).

Induction of Allogeneic Islet Tolerance in a Large-Animal Model

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