Permanent acceptance of both cardiac and skin allografts using a mild conditioning regimen for the induction of stable mixed chimerism in mice

Pel, Melissa van; Hilbrands, Luuk B.; Smits, Debby; Breugel, Danielle W.J.G. van; Eck, Mathijs van; Boog, Claire J. P.

doi:10.1016/s0966-3274(02)00147-8

Cited by 3 publications

(3 citation statements)

References 33 publications

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“…A single in vivo study demonstrated that transfer of G-CSF-mobilized donor leukocytes following allogeneic heart transplantation in a rat model led to increased IL-10 (and reduced IFN-␥ and IL-2) within grafts and significantly prolonged graft survival. 39 The mechanism of this effect was not established, however, and tolerance may reflect the induction of a mixed chimeric state, as previously described, [40][41][42] rather than the presence of regulatory function. G-CSF may alter T-cell function either directly 10 or indirectly by way of expansion of APCs or other cells of the innate immune system.…”

Section: Discussionmentioning

confidence: 92%

Donor treatment with pegylated G-CSF augments the generation of IL-10-producing regulatory T cells and promotes transplantation tolerance

Morris

MacDonald²,

Rowe³

et al. 2004

Blood

119

102

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We investigated whether the protection from graft-versus-host disease (GVHD) afforded by donor treatment with granulocyte colony-stimulating factor (G-CSF) could be enhanced by dose escalation. Donor treatment with human G-CSF prevented GVHD in the B6 → B6D2F1 murine model in a dose-dependent fashion, and murine G-CSF provided equivalent protection from GVHD at 10-fold lower doses. Donor pretreatment with a single dose of pegylated G-CSF (peg-G-CSF) prevented GVHD to a significantly greater extent than standard G-CSF (survival, 75% versus 11%, P < .001). Donor T cells from peg-G-CSF-treated donors failed to proliferate to alloantigen and inhibited the responses of control T cells in an interleukin 10 (IL-10)-dependent fashion in vitro. T cells from peg-G-CSF-treated IL-10-/- donors induced lethal GVHD; T cells from peg-G-CSF-treated wild-type (wt) donors promoted long-term survival. Whereas T cells from peg-G-CSF wt donors were able to regulate GVHD induced by T cells from control-treated donors, T cells from G-CSF-treated wt donors and peg-G-CSF-treated IL-10-/- donors did not prevent mortality. Thus, peg-G-CSF is markedly superior to standard G-CSF for the prevention of GVHD following allogeneic stem cell transplantation (SCT), due to the generation of IL-10-producing regulatory T cells. These data support prospective clinical trials of peg-G-CSF-mobilized allogeneic blood SCT. (Blood. 2004;103:3573-3581)

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Section: Discussionmentioning

confidence: 92%

Donor treatment with pegylated G-CSF augments the generation of IL-10-producing regulatory T cells and promotes transplantation tolerance

Morris

MacDonald²,

Rowe³

et al. 2004

Blood

119

102

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“…[6][7][8] In addition, conditioning via this regimen enables the permanent acceptance of vascularized allografts as well as skin grafts. 9 Although the exact long-term risk to a patient receiving a sublethal dose of TBI is presently unknown, it may be associated with substantial morbidity. It would therefore be desirable to eliminate TBI from a clinical tolerance protocol.…”

mentioning

confidence: 99%

Toward a myeloablative regimen with clinical potential: II. Treosulfan induces specific skin graft tolerance across haploidentical MHC barriers

Pel

Breugel

Vos

et al. 2003

Bone Marrow Transplant

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Summary:Treosulfan is a water-soluble structural analog of busulfan, acting as a prodrug of alkylating epoxide species. It does not induce severe hepatotoxicity or veno-occlusive disease at or above the maximum tolerated dose, lacks significant nonhematological toxicity and has a limited organ toxicity. It is mainly indicated for the treatment of patients with ovarian cancer. In the present study, we report that permanent donor-specific tolerance and stable mixed multilineage chimerism can successfully be achieved across haploidentical MHC barriers when Treosulfan is administered in combination with anti-T-cell mAb and T-celldepleted donor bone marrow cells. Furthermore, we show that less T-cell suppression is required when Treosulfan is included in the conditioning regimen. In conclusion, Treosulfan is a well-tolerated myeloablative agent with a low toxicity, and is a promising candidate drug for conditioning prior to bone marrow transplantation.

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“…In our study, allograft recipients with VBMT (group 5), and those with VBMT augmented with BMT (group 6), accepted the skin grafts from Lewis and BN rats; hovewer, the time of acceptance was limited to 35 days post-transplant. This result indicates that while stable mixed chimerism 31 can be established across a full MHC barrier under short-term (7-day) treatment with ab-TCR mAb and CsA; however it is not sufficient to maintain tolerance in this model. Tsuchida et al 32 reported that skin allografts in rats that simultaneously received vascularized limb allografts were rejected more slowly.…”

Section: Discussionmentioning

confidence: 84%

Chimerism induction in vascularized bone marrow transplants augmented with bone marrow cells

Arslan¹,

Klimczak²,

Siemionow³

2007

Microsurgery

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Composite tissue allografts (CTAs) are currently accepted in the clinic; however, long-term immunosuppression is still needed for allograft survival. The presence of donor-specific chimerism may induce tolerance. Thirty-six vascularized bone marrow transplantation (VBMT) allotransplantation were performed across MHC barrier under short-term protocol of 7-day alphabeta-TCRmAb and Cyclosporin A therapy to determine the efficacy of VBMT alone and VBMT augmented with donor bone marrow transplantation (BMT) in chimerism induction. Flow cytometry analysis revealed that VBMT supported with donor BMT directly into the bone resulted in chimerism augmentation and maintenance compared to VBMT. In vivo and in vitro tolerance testing showed prolonged survival of donor skin graft up to 35 days and moderate reactivity in MLR assay that suggests only tolerance induction. Transplantation of vascularized bone without chronic immunosuppression provides a substantial source of bone marrow cells, leading to the development of stable donor-specific chimerism.

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Permanent acceptance of both cardiac and skin allografts using a mild conditioning regimen for the induction of stable mixed chimerism in mice

Cited by 3 publications

References 33 publications

Donor treatment with pegylated G-CSF augments the generation of IL-10-producing regulatory T cells and promotes transplantation tolerance

Donor treatment with pegylated G-CSF augments the generation of IL-10-producing regulatory T cells and promotes transplantation tolerance

Toward a myeloablative regimen with clinical potential: II. Treosulfan induces specific skin graft tolerance across haploidentical MHC barriers

Chimerism induction in vascularized bone marrow transplants augmented with bone marrow cells

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