Immunologic Benefits of Spleen Transplantation in the Absence of Graft-Versus-Host Disease

To the Editor:

With interest we read the paper by Tzakis et al, recently published in your journal,¹ that summarizes the evolution and current status of clinical multivisceral transplantation. One of the conclusions of the authors is that a multivisceral graft seems to facilitate engraftment of organs, suggesting that this procedure offers a degree of immunologic advantage. As the authors state in their discussion, this advantage could be partly attributed to the inclusion of the spleen in the graft, and they referred to a previous study of ours relating to spleen transplantation.²

We would like to comment on some of the immunologic aspects of spleen transplantation, particularly with regard to its effect in inducing a state of donor-specific unresponsiveness, the lack of associated graft-versus-host-disease (GVHD), and the incidence of posttransplantation lymphoproliferative disease (PTLD) (as discussed in the panel discussions on pages 491–493).¹

Following an extensive review of the literature of spleen transplantation, mainly in rodent models,³ we and colleagues carried out spleen allotransplantation across minor-mismatch, MHC class 1 and MHC full-mismatch barriers in a preclinical miniature swine model.^4–6 Recipient pigs of MHC-mismatched grafts received induction therapy consisting of a low dose of whole body irradiation (100 cGy on day −2), which is nonmyeloablative,⁶ and thymic irradiation (700 cGy on day −1); maintenance immunosuppression consisted of cyclosporine monotherapy for 45 days only.

In all recipients of successful spleen grafts, multilineage chimerism was detected in the blood for periods up to 6 months,⁶ and donor cells were identified in the bone marrow and thymus. In vitro assays, such as mixed leukocyte reactivity and cell-mediated lympholysis, indicated that donor-specific T-cell reactivity was suppressed while third-party responses were maintained intact.⁶ In 2 recipients of spleen transplants, kidney transplantation was subsequently performed from a pig MHC-matched to the original spleen donor, without exogenous immunosuppression. Although these grafts eventually failed from uncertain cause (although not from classic rejection) after >4 and >7 months, respectively, this was in great contrast to kidney grafts in control asplenic nonimmunosuppressed recipients that were rejected within 4 and 15 days, respectively.⁶

A very mild, transient, and self-limiting form of cutaneous GVHD was observed in a minority of recipients, but no serious manifestations of this condition were seen even in pigs that demonstrated >50% donor T-cell chimerism.^4,6

Although none of the patients with a spleen as part of their multivisceral transplant developed PTLD in the series reported by Tzakis et al,¹ we observed 2 cases in pigs with spleen transplants, but only when the levels of cyclosporine therapy had been excessively high.⁷

In conclusion, we agree with the authors of this paper in believing that a spleen allograft has immunologic benefits and has the potential to induce a state of unresponsiveness not only to itself but also to other donor-specific organs. Using the regimen we followed, even when the level of chimerism was high, GVHD was not a problem, and PTLD could be avoided by careful monitoring of immunosuppressive drug levels. We think that spleen transplantation has considerable potential as a means of inducing a state of tolerance to other donor-specific organs and is worthy of further investigation.

Frank J. M. F. Dor, MD*
David K. C. Cooper, MD, PhD, FRCS†
*Department of Surgery
Erasmus MC
Rotterdam, The Netherlands
†Thomas E. Starzl Transplantation Institute
University of Pittsburgh Medical Center
Pittsburgh, PA