Split tolerance to a composite tissue allograft in a swine model

Mathes, David W.; Randolph, Mark A.; Solari, Mario G.; Nazzal, Jamal A.; Nielsen, G. Petur; Arn, J S; Sachs, David H.; Lee, W. P.Andrew

doi:10.1097/00007890-200301150-00005

Cited by 124 publications

(82 citation statements)

References 25 publications

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“…Indeed, failure to definitively close the burn wound is a major contributor to prolonged length of stay, complications, and death (64). Little progress has been made in using allogeneic skin for permanent wound coverage (65,66). Homeostatic proliferation of T cells is recognized as an important mechanism preventing the induction of allogeneic tolerance (45,67) and may provide a mechanism for why severely immunocompromised burn patients are able to reject allogeneic skin grafts (29,65).…”

Section: Discussionmentioning

confidence: 99%

Lymphopenia-Induced Homeostatic Proliferation of CD8+ T Cells Is a Mechanism for Effective Allogeneic Skin Graft Rejection following Burn Injury

Maile

Barnes²,

Nielsen³

et al. 2006

The Journal of Immunology

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Burn patients are immunocompromised yet paradoxically are able to effectively reject allogeneic skin grafts. Failure to close a massive burn wound leads to sepsis and multiple system organ failure. Immune suppression early (3 days) after burn injury is associated with glucocorticoid-mediated T cell apoptosis and anti-inflammatory cytokine responses. Using a mouse model of burn injury, we show CD8+ T cell hyperresponsiveness late (14 days) after burn injury. This is associated with a CD8+ T cell pro- and anti-inflammatory cytokine secretion profile, peripheral lymphopenia, and accumulation of a rapidly cycling, hyperresponsive memory-like CD8+CD44+ IL-7R− T cells which do not require costimulation for effective Ag response. Adoptive transfer of allospecific CD8+ T cells purified 14 days postburn results in enhanced allogeneic skin graft rejection in unburned recipient mice. Chemical blockade of glucocorticoid-induced lymphocyte apoptosis early after burn injury abolishes both the late homeostatic accumulation of CD8+ memory-like T cells and the associated enhanced proinflammatory CD8+ T cell response, but not the late enhanced CD8+ anti-inflammatory response. These data suggest a mechanism for the dynamic CD8+ T cell response following injury involving an interaction between activation, apoptosis, and cellular regeneration with broad clinical implications for allogeneic skin grafting and sepsis.

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Section: Discussionmentioning

confidence: 99%

Lymphopenia-Induced Homeostatic Proliferation of CD8+ T Cells Is a Mechanism for Effective Allogeneic Skin Graft Rejection following Burn Injury

Maile

Barnes²,

Nielsen³

et al. 2006

The Journal of Immunology

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“…B6 combination used in the current study crosses both MHC and multiple minor antigen barriers. Minor antigens, in particular skin specific antigens, failed to be tolerized in some previously reported chimerism studies (45,46). Therefore, we transplanted B10.D2 BM (H-2 d ) which is MHC-mismatched to B6 but shares the same minor antigen background into B6 recipients (H-2 b ).…”

Section: Donor Cells Lacking Cd40 Fail To Tolerize Recipient Cd4 T Cellsmentioning

confidence: 99%

Rapamycin and CTLA4Ig Synergize to Induce Stable Mixed Chimerism Without the Need for CD40 Blockade

Pilat

Klaus

Schwarz

et al. 2015

American Journal of Transplantation

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y Both authors contributed equally.The mixed chimerism approach achieves donor-specific tolerance in organ transplantation, but clinical use is inhibited by the toxicities of current bone marrow (BM) transplantation (BMT) protocols. Blocking the CD40: CD154 pathway with anti-CD154 monoclonal antibodies (mAbs) is exceptionally potent in inducing mixed chimerism, but these mAbs are clinically not available. Defining the roles of donor and recipient CD40 in a murine allogeneic BMT model, we show that CD4 or CD8 activation through an intact direct or CD4 T cell activation through the indirect pathway is sufficient to trigger BM rejection despite CTLA4Ig treatment. In the absence of CD4 T cells, CD8 T cell activation via the direct pathway, in contrast, leads to a state of split tolerance. Interruption of the CD40 signals in both the direct and indirect pathway of allorecognition or lack of recipient CD154 is required for the induction of chimerism and tolerance. We developed a novel BMT protocol that induces mixed chimerism and donor-specific tolerance to fully mismatched cardiac allografts relying on CD28 costimulation blockade and mTOR inhibition without targeting the CD40 pathway. Notably, MHC-mismatched/minor antigen-matched skin grafts survive indefinitely whereas fully mismatched grafts are rejected, suggesting that non-MHC antigens cause graft rejection and split tolerance.

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“…Rejection was observed in most animals, however, when skin was incorporated in the CTA, and the authors theorized that topical cyclosporine may be a necessary component of a clinical application of this regimen. 38,39 Avoiding Rejection I: The Graft Since MHC antigens are expressed on the surface of cells, treatments which remove the cellular component from tissues of allogeneic origin can result in allografts which are relatively well tolerated by the recipient. Cadaveric bone is the most commonly used allogeneic material.…”

Section: Avoiding Rejection Ii: the Recipientmentioning

confidence: 99%

Cryopreservation and the age of the allotransplant

Rinker¹

2009

Organogenesis

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Split tolerance to a composite tissue allograft in a swine model

Cited by 124 publications

References 25 publications

Lymphopenia-Induced Homeostatic Proliferation of CD8+ T Cells Is a Mechanism for Effective Allogeneic Skin Graft Rejection following Burn Injury

Lymphopenia-Induced Homeostatic Proliferation of CD8+ T Cells Is a Mechanism for Effective Allogeneic Skin Graft Rejection following Burn Injury

Rapamycin and CTLA4Ig Synergize to Induce Stable Mixed Chimerism Without the Need for CD40 Blockade

Cryopreservation and the age of the allotransplant

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