Original article: cardiovascular
A clinically relevant CTLA4-Ig-based regimen induces chimerism and tolerance to heart grafts

Presented at the Thirty-seventh Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 29–31, 2001.
https://doi.org/10.1016/S0003-4975(01)03066-1Get rights and content

Abstract

Background. We determined whether a nontoxic CTLA4-Ig-based conditioning regimen effected mixed chimerism and donor-specific tolerance when heart and bone marrow were transplanted simultaneously.

Methods. Fully mismatched rat strain combinations were used. Recipients received total-body irradiation (300 centigrays), bone marrow (108 cells), and cardiac transplants from the donor on day 0. Subsequently, recipient animals received CTLA4-Ig (2 mg/kg, every other day, × 5 doses), tacrolimus (1 mg/kg/day; days 0 to 9), and one dose (10 mg) of antilymphocyte serum on day 10.

Results. All bone marrow recipients (n = 7) developed mixed chimerism (mean = 25% ± 9% at 1 year) and accepted cardiac allografts permanently (> 375 ± 32 days). Recipients that received conditioning regimen but no bone marrow (n = 5) rejected donor hearts within 51 ± 13 days (p < 0.01). Recipients that accepted heart grafts also permanently accepted (> 180 days) donor-specific skin grafts, but rapidly rejected (< 10 days) third-party skin grafts.

Conclusions. A nontoxic CTLA4-Ig-based conditioning regimen effects mixed chimerism and donor-specific tolerance when heart and bone marrow are transplanted simultaneously. This regimen may have clinical application.

Section snippets

Animals

Six- to 8-week-old major histocompatibility complex (MHC) and minor antigen-mismatched Wistar Furth (WF; RT1.Au), August Copenhagen Irish (ACI; RT1.Aa), and Lewis (RT1.A1) rats were purchased from Harlan Sprague Dawley (Indianapolis, IN) and housed in a pathogen-free facility. All animals were treated in compliance with the Principles of Laboratory Animal Care, formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals, prepared by the

Stable mixed hematopoietic chimerism and robust donor-specific tolerance to heart allografts

One hundred percent (7 of 7) of animals conditioned with the CTLA4-Ig-based regimen developed MC. The MC was stable with a mean donor chimerism of 25% ± 9% at 1 year (Table 1). There was no conditioning-related morbidity or mortality. None of the animals showed clinical or histological evidence for acute or chronic GVHD. All bone marrow recipients (n = 7) exhibited donor-specific tolerance to cardiac allografts (mean graft survival time: > 375.0 ± 32.0 days; Table 1, group 3). In contrast, all

Comment

In this study, we have demonstrated that a nontoxic CTLA4-Ig-based conditioning regimen effects mixed chimerism and donor-specific tolerance when heart and bone marrow are transplanted simultaneously. The conditioning regimen consists of CTLA4-Ig (which blocks the CD28:B7 costimulatory pathway), tacrolimus, antithymocyte globulin, and low-dose (300 cGy) total-body irradiation. This conditioning regimen was well tolerated by the animal. No animal developed acute or chronic GVHD. All animals that

Acknowledgements

This work was supported in part by grants from the American Heart Association (National Center; 960144590) and the Thoracic Surgery Research Foundation Fellowship Award to Mohan Thanikachalam.

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