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J Heart Lung Transplant. 1996 Sep;15(9):928-35.

Preventing allograft rejection with CTLA4IG: effect of donor-specific transfusion route or timing.

Author information

1
Section of Thoracic Surgery, University of Michigan Medical Center, Ann Arbor, USA.

Abstract

BACKGROUND:

Tolerance to alloantigen in transplant recipients could remove life-long dependence on immunosuppression. Evidence suggests that T-cell responses to alloantigen are dependent not only on T-cell receptor activation but also on costimulation by means of the CD28 receptor. The natural ligands for CD28, expressed on antigen-presenting cells, are B7 family members. CTLA4Ig (a soluble CD28 receptor analog) preferentially binds B7-1 and B7-2 and inhibits CD28 activation. Theoretically, T-cell receptor activation in the presence of alloantigen during CTLA4Ig blockade of CD28-B7 costimulation could render T cells tolerant to that specific alloantigen. In vivo CTLA4Ig significantly increases allograft survival times and can lead to transplantation tolerance. In the rat cardiac allograft model, donor-specific transfusion must be combined with CTLA4Ig to induce tolerance. Previously our laboratory has shown that timing is crucial in the induction of tolerance.

METHODS:

We examined the effect of differing routes (intravenous, portal vein, or intrathymic), as well as timing (before, at, and after transplantation), of donor-specific transfusion on its ability to synergize with CTLA4Ig using a rat heterotopic major histocompatibility complex-mismatch heart transplant model.

RESULTS:

We found that tolerance induced by CTLA4Ig and donor-specific transfusion was antigen specific and that timing, but not route of donor-specific antigen administration, had an impact on tolerance induction. Intravenous donor-specific transfusion had a beneficial effect on allograft survival equal to portal vein and intrathymic routes, which have been believed to be more tolerogenic.

CONCLUSIONS:

Almost universal engraftment can be induced with a combination of intravenous donor-specific transfusion at transplantation plus inhibition of CD28 activation by CTLA4Ig 48 hours after transplantation-a regimen which could have clinical application.

PMID:
8889989
[Indexed for MEDLINE]

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