Differential survival of skin and heart allografts in radiation chimaeras provides further evidence for Sk histocompatibility antigen

Steinmuller, David; Lofgreen, Jane S.

doi:10.1038/248796a0

Cited by 48 publications

(32 citation statements)

References 8 publications

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“…The other animal tested in the same way showed permanent donor skin survival. These data are consistent with what is known about skin-specific antigens in mice (52)(53)(54). Because it is likely that only a few alleles for such skin-specific anti-gens exist within our swine herd, some animals could be expected to share common alleles by chance, and therefore a certain percentage of chimeric animals might be expected to accept skin grafts, whereas others would reject.…”

supporting

confidence: 77%

Mixed chimerism and tolerance without whole body irradiation in a large animal model

Fuchimoto¹,

Huang²,

Yamada³

et al. 2000

J. Clin. Invest.

184

120

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Mixed hematopoietic chimerism may provide a treatment for patients with nonmalignant hematologic diseases, and may tolerize patients to organ allografts without requiring chronic immunosuppression. However, the toxicity of the usual conditioning regimens has limited the clinical applicability of this approach. These regimens generally include some level of whole body irradiation (WBI), which is thought to facilitate engraftment either by making room for donor hematopoietic stem cells or by providing sufficient host immunosuppression to enable donor cells to engraft. Here, we have established mixed chimerism across both minor and major histocompatibility barriers in swine, by using high doses of peripheral blood stem cells in the absence of WBI. After mixed chimerism was established, swine leukocyte antigen-matched (SLA-matched) donor skin grafts were tolerated and maintained for a prolonged period, whereas third-party SLA-matched skin was rejected promptly. Donor-matched kidney allografts were also accepted without additional immunosuppression. Because of its low toxicity, this approach has potential for a wide range of clinical applications. Our data may indicate that niches for engrafting stem cells are filled by mass action and that WBI, which serves to empty some of these niches, can be omitted if the donor inoculum is sufficiently large and if adequate host T-cell depletion is achieved before transplant.

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supporting

confidence: 77%

Mixed chimerism and tolerance without whole body irradiation in a large animal model

Fuchimoto¹,

Huang²,

Yamada³

et al. 2000

J. Clin. Invest.

184

120

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“…Heart allograft integrity, however, was never compromised in chimeric recipients with chronic skin graft rejection, suggesting lack of cross-reactivity between skin and heart Ags. Similar conclusions were drawn from earlier studies that compared heart and skin graft survival in radiation chimeras, although histological screening for heart arteriopathy was not reported (35). Although a short 2-day interval between BMTx and skin Tx substantially delayed or prevented chronic rejection, it did not achieve complete protection.…”

Section: Discussionsupporting

confidence: 70%

“…Although only ϳ5% of all skin allografts transplanted 3 mo after BMTx were also protected from chronic rejection, early studies by Steinmuller and Lofgreen (35) suggested that heart allografts may not pose the same problems of tissue-specific Ags as observed for skin grafts. While our experiments were ongoing, one study reported protection from acute but not from chronic heart graft rejection by established chimeras (36), whereas in another system both acute and chronic heart allograft rejection were prevented by BMTx, albeit with a protocol that included costimulation blockade beyond chimerism induction at the time of heart Tx (37).…”

Section: Stable Hemopoietic Chimerism Prevents Chronic Heart Allografmentioning

confidence: 99%

Combinations of Anti-LFA-1, Everolimus, Anti-CD40 Ligand, and Allogeneic Bone Marrow Induce Central Transplantation Tolerance through Hemopoietic Chimerism, Including Protection from Chronic Heart Allograft Rejection

Metzler

Gfeller

Bigaud

et al. 2004

The Journal of Immunology

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Central transplantation tolerance through hemopoietic chimerism initially requires inhibition of allogeneic stem cell or bone marrow (BM) rejection, as previously achieved in murine models by combinations of T cell costimulation blockade. We have evaluated LFA-1 blockade as part of regimens to support mixed hemopoietic chimerism development upon fully allogeneic BALB/c BM transfer to nonirradiated busulfan-treated B6 recipient mice. Combining anti-LFA-1 with anti-CD40 ligand (CD40L) induced high incidences and levels of stable multilineage hemopoietic chimerism comparable to chimerism achieved with anti-CD40L and everolimus (40-O-(2-hydroxyethyl)-rapamycin) under conditions where neither Ab alone was effective. The combination of anti-LFA-1 with everolimus also resulted in high levels of chimerism, albeit with a lower incidence of stability. Inhibition of acute allograft rejection critically depended on chimerism stability, even if maintained at very low levels around 1%, as was the case for some recipients without busulfan conditioning. Chimerism stability correlated with a significant donor BM-dependent loss of host-derived Vβ11+ T cells 3 mo after BM transplantation (Tx). Combinations of anti-CD40L with anti-LFA-1 or everolimus also prevented acute rejection of skin allografts transplanted before established chimerism, albeit not independently of allospecific BMTx. All skin and heart allografts transplanted to stable chimeras 3 and 5 mo after BMTx, respectively, were protected from acute rejection. Moreover, this included prevention of heart allograft vascular intimal thickening (“chronic rejection”).

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“…Why did T cell-deficient BMT recipients reject skin grafts, but not chimeric donor cells, while wtB6/6.5Gy BMT recipients rejected both skin grafts and chimeric cells? Involvement of skin-specific Ag (18,19) was ruled out as cause of skin graft rejection because the degree of in vivo proliferation correlated well with specific skin allograft survival and adoptive transfer of wt donor T cells alone without exposure to skin Ag-restored tolerance to skin allografts. In vivo MLR showed that the responder frequency of donor-reactive CD4 ϩ T cells was smaller in T cell-deficient BMT recipients than that in wtB6/6.5Gy BMT recipients.…”

Section: Discussionmentioning

confidence: 99%

Dissociation of Hemopoietic Chimerism and Allograft Tolerance After Allogeneic Bone Marrow Transplantation

Umemura¹,

Morita²,

Li³

et al. 2001

The Journal of Immunology

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Creation of stable hemopoietic chimerism has been considered to be a prerequisite for allograft tolerance after bone marrow transplantation (BMT). In this study, we demonstrated that allogeneic BMT with bone marrow cells (BMC) prepared from either knockout mice deficient in both CD4 and CD8 T cells or CD3E-transgenic mice lacking both T cells and NK cells maintained a high degree of chimerism, but failed to induce tolerance to donor-specific wild-type skin grafts. Lymphocytes from mice reconstituted with T cell-deficient BMC proliferated when they were injected into irradiated donor strain mice, whereas lymphocytes from mice reconstituted with wild-type BMC were unresponsive to donor alloantigens. Donor-specific allograft tolerance was restored when donor-type T cells were adoptively transferred to recipient mice given T cell-deficient BMC. These results show that donor T cell engraftment is required for induction of allograft tolerance, but not for creation of continuous hemopoietic chimerism after allogeneic BMT, and that a high degree of chimerism is not necessarily associated with specific allograft tolerance.

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Differential survival of skin and heart allografts in radiation chimaeras provides further evidence for Sk histocompatibility antigen

Cited by 48 publications

References 8 publications

Mixed chimerism and tolerance without whole body irradiation in a large animal model

Mixed chimerism and tolerance without whole body irradiation in a large animal model

Combinations of Anti-LFA-1, Everolimus, Anti-CD40 Ligand, and Allogeneic Bone Marrow Induce Central Transplantation Tolerance through Hemopoietic Chimerism, Including Protection from Chronic Heart Allograft Rejection

Dissociation of Hemopoietic Chimerism and Allograft Tolerance After Allogeneic Bone Marrow Transplantation

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