The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/8/497/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 4, August 18, 1997 497-506

Article

Role of the Thymus in Transplantation Tolerance in Miniature Swine. I. Requirement of the Thymus for Rapid and Stable Induction of Tolerance to Class I–mismatched Renal Allografts

Kazuhiko Yamada*, Pierre R. Gianello*, Francesco L. Ierino*, Thomas Lorf*, Akira Shimizu{ddagger}, Shane Meehan{ddagger}, Robert B. Colvin{ddagger}, and David H. Sachs*

From the * Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, 02129; and {ddagger} Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, 02114

The almost uniform failure in transplant patients of tolerance-inducing regimens that have been found to be effective in rodents, has made it necessary to examine large animal models before testing of new approaches clinically. Miniature swine have been shown to share many relevant immunologic parameters with humans, and because of their reproducible genetics, have proved extremely useful in providing such a large animal model. We have previously shown that indefinite systemic tolerance to renal allografts in miniature swine is induced in 100% of cases across a two-haplotype class I plus minor histocompatibility antigen disparity by a 12-d course of Cyclosporine A (CyA), in contrast to irreversible rejection observed uniformly without CyA treatment. In the present study, we have examined the role of the thymus during the induction of tolerance by performing a complete thymectomy 21 d before renal transplantation. This analysis demonstrated a striking difference between thymectomized and nonthymectomized animals. Thymectomized swine developed acute cellular rejection characterized by a T cell (CD25+) infiltrate, tubulitis, endothelialitis and glomerulitis, and anti–donor CTL reactivity in vitro. Nonthymectomized and sham thymectomized animals had a mild T cell infiltrate with few CD25+ cells and no anti–donor CTL response in vitro. These results indicate that the thymus is required for rapid and stable induction of tolerance.

Address correspondence to Dr. David H. Sachs, Transplantation Biology Research Center, Massachusetts General Hospital, MGH-East, Bldg. 149-9019, 13th St., Boston, MA 02129. PHone: 617-726-4065; FAX: 617-726-4067.

1 Abbreviations used in this paper: CD, cluster of differentiation; CML, cell-mediated lysis; CyA, Cyclosporine A; GIC, graft-infiltrating cell; PAS, periodic acid–Schiff; POD, postoperative day; PSL, percent specific lysis; SLA, swine lymphocyte antigen.


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