The CD28 peptidemimic can induce mixed chimerism and prolong the survival of cardiac allografts

Composite tissue allotransplantation holds a great potential for providing increased knowledge of anatomy and microsurgical experience for life-enhancing reconstructions. Many transplant cases around the world have made this a clinical reality at the present time. Composite tissue allotransplants contain multiple tissue types, including bone, muscle, vessels, nerves, skin, and immune cells and bear a huge antigenic load. Although immunosuppressive drugs are applied successfully to prevent allograft rejection, their side effects pose a barrier to worldwide use. Bone marrow therapy in many tolerance induction protocols, therefore, provides a guide to reaching the target of permanent immunotolerance. Multiple studies suggest that bone marrow is immunomodulatory and may facilitate allograft acceptance. In this review, bone marrow based therapy protocols of clinical and experimental models are presented in two major categories: solid organ and composite tissue transplantation.

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“…30 Chen et al demonstrated long-term cardiac allograft tolerance using BM cells and splenocytes with CD 28 costimulatory blockade. 31 …”

Section: Experimental Solid Organ Transplantations Heartmentioning

confidence: 99%

Chimerism and bone marrow based therapies in transplantation

Siemionow

Nasır

2007

Microsurgery

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“…Its use is limited by organ availability and by several factors after transplant. These include infections related to immunosuppression, as well as acute and chronic immune rejection, including cardiac allograft vasculopathy (CAV) 3 and secondary organ morbidity. CAV is a major challenge that occurs in Ͼ50% of heart transplant recipients in the first few years after surgery (1,2).…”

mentioning

confidence: 99%

“…CAV is a major challenge that occurs in Ͼ50% of heart transplant recipients in the first few years after surgery (1,2). Attempts to develop long-term tolerance for heart transplants have involved central strategies, such as "mixed chimerism", and peripheral strategies, such as enhancement of regulatory T cells and costimulatory blockade (3)(4)(5).…”

mentioning

confidence: 99%

Long-Term Cardiac Allograft Survival across an MHC Mismatch after “Pruning” of Alloreactive CD4 T Cells

Watson

Zhang

et al. 2008

The Journal of Immunology

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Specific tolerance to allografts has been achieved by a variety of means. We have previously shown that ex vivo removal of dividing CD4+ T cells from an MLR or “pruning” delays skin allograft rejection. We tested pruning of alloreactive T cells as a strategy for retaining a broad T cell repertoire while removing alloreactive T cells in a model of cardiac allograft transplant. Using CFSE staining of responder BALB/c cells with stimulator C57BL/6 cells in an MLR, SCID mice were reconstituted with either dividing (D) or nondividing (ND) CD4+ T cells derived from an MLR and then challenged with heterotopic cardiac allografts. Mice reconstituted with D CD4+ T cells rejected cardiac allografts from the stimulator strain with a median survival time (MST) of 29 days, while mice reconstituted with ND CD4+ T cells maintained allografts from the stimulator strain (MST of >100 days) while rejecting third-party allografts (B10.BR) (MST = 11 days). ELISPOT assays demonstrate donor-specific hyporesponsiveness of the ND CD4+ T cells. TCR β-chain V region (TRBV) repertoire analysis demonstrates clonal expansion within both rejecting D cardiac allografts and ND cardiac allografts surviving for the long-term. Histology showed greater allograft infiltration by the D CD4+ T cells. The surviving ND cardiac allografts demonstrated reduced cellular infiltration and reduced incidence of allograft vasculopathy, but with the development of chronic fibrosis. Thus, pruning of alloreactive T cells allows long-term-specific cardiac allograft survival while retaining the ability to reject third-party allografts.

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