Bishop, GA

McCaughan, GW

Shell, AGR

Starzl, T

Sun, J

English

D-Scholarship@Pitt

0041-1337/98/6602-272$03.00/0 TRANSPLANTATION Copyright © 1998 by Williams & Wilkins Vol. 66, 272-273, No.2, July 27, 1998 mrin~d in U.S.A Transplan tation ® LETIERS TO THE EDITOR EFFECT OF TROGLITAZONE ON CYCLOSPORINE WHOLE BLOOD LEVELS Troglitazone (TGZ; Rezulin, Parke-Davis, Morris Plains, NJ) is a thiazolidinedione antihyperglycemic agent that has been shown to decrease hemoglobin A1c and decrease insulin requirements in patients with type 2 diabetes (1-4). It in-creases tissue sensitivity to insulin and decreases hepatic glucose production but does not increase insulin secretion (5). At doses used clinically, troglitazone decreases plasma levels of ethinyl estradiol and norethindrone in oral contraceptives by 30%, and terfenadine by 50-70%, possibly by inducing hepatic metabolism by CYP3A4 (6). However, clinically sig-nificant interactions with other drugs metabolized by CYP3A4, such as cyclosporine (CsA; Neoral, Novartis, East Hanover, New Jersey), have not been described in the liter-ature. We report the effects of troglitazone on CsA whole blood levels in 11 stable renal transplant patients. The medical records of all renal transplant recipients re-ceiving TGZ at our hospital were reviewed. Of 12 patients, 11 had follow-up CsA blood levels available for analysis. All results are reported as mean :<:: SD. The mean age was 54.5:<::11.6 years, and the mean time since transplantation was 20.5:!::: 18.2 months. All patients were receiving a stable CsA dose, and only one patient was receiving a drug known to affect the metabolism of CsA (diltiazem). The TGZ dose was 200-400 mg/day. The mean CsA whole blood level fell from 205:<::42 ng/ml at the time TGZ was initiated to 139:<::65 ng/ml after 1 week, a decrease of 32% (P=0.0015, paired t test). Six patients (50%) required a CsA dosage increase of 50-150 mg/day between 1 and 7 weeks after initiation of TGZ. The mean CsA dose at the time TGZ was initiated was 358:<::93 ng/ml, compared with 392:<:: 100 ng/ml after 4 weeks (P=0.05, paired t test) and 404:<::92 ng/ml after 12 weeks (P=0.03, paired t test). There were no concomitant changes in medications or obvious alterations in gastrointestinal function that could explain the decrease in CsA blood levels. Despite continuous administration of diltiazem in one pa-tient, the CsA level fell by 53% after initiation of TGZ, and 7 weeks after initiation of TGZ, he suffered a Banff grade II rejection with vasculitis requiring treatment with OKT3 (Or-thoclone OKT3, Ortho Biotech, Raritan, NJ). The serum cre-atinine concentration increased 30% from baseline in one other patient and was attributed to increased CsA dosage. Troglitazone may be a useful antihyperglycemic agent in some transplant recipients with type 2 diabetes. However, it can lead to a reduction of CsA whole blood levels, possibly by inducing hepatic metabolism by CYP3A4. We have not used troglitazone in combination with tacrolimus to date, but we expect that the potential for decreased tacrolimus levels ex-ists. Therefore, we recommend more frequent monitoring of either CsA or tacrolimus levels as appropriate after initiation of troglitazone, until a new steady state immunophilin level is achieved. SANDRA J. BURGESS GARY G. SINGER DANIEL C. BRENNAN l Department of Pharmacy Renal Division Barnes-Jewish Hospital Washington University School of Medicine St. Louis, Missouri 63110 1 Address correspondence to: Daniel C. Brennan, MD, 1 Barnes-Jewish Hospital Plaza, Suite 6107, Queeny Tower, St. Louis, MO 63110. REFERENCES 1. Iwamoto Y, Kosaka K, Kuzuya T, et al. Effects oftroglitazone: a new hypoglycemic agent in patients with NIDDM poorly con-trolled by diet therapy. Diabetes Care 1996; 19(2): 151. 2. Iwamoto Y, Kosaka K, Kuzuya T, et al. Effect of combination therapy oftroglitazone and sulfonylureas in patients with type 2 diabetes who were poorly controlled by sulfonyl-urea therapy alone. Diabetes Med 1996; 13: 365. 3. Kumar S, Boulton AJ, Beck-Nielsen H, et al. Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Diabetologia 1996; 39(6): 701. 4. Anonymous. Troglitazone for non-insulin-dependent diabetes mellitus. Med Lett Drugs Ther 1997; 39(1001): 49. 5. Suter SL, Nolan TJ, Wallace P, et aI. Metabolic effects of new oral hypoglycemic agent CS-045 in NIDDM subjects. Diabetes Care 1992; 15: 193. 6. Rezulin™, Troglitazone [package insertl. Morris Plains, NJ: Parke-Davis, 1997. CHIMERISM AND CLONAL EXHAUSTION In their recent review, Bishop et al. (1) appropriately em-phasized the essential role of donor leukocyte chimerism in the induction of "high-doselactivation-associated tolerance" (clonal exhaustion). While generously citing our discovery of persistent post-organ transplant chimerism (2, 3), the au-thors attributed to us a hypothesis (i.e., "GVH-induced toler-ance associated with chimerism" [1)) that could be construed as fundamentally different than theirs. 272 • r July 27, 1998 LETIERS TO THE EDITOR 273 In actuality, the events after organ transplantation were explained in the cited articles "by responses of co-existing donor and recipient immune cells, each to the other, causing reciprocal clonal expansion, followed by peripheral clonal deletion" (2, 3). Thus, there is no inconsistency of the inter-pretations published from the Pittsburgh and Sydney labo-ratories except for the belief of Bishop et a1. (1) that the clonal exhaustion is solely of the host leukocyte population. In our view, a mutually exhausting double immune reaction (host versus graft and graft versus host) must be invoked to ex-plain the outcome in most transplant situations (2-5). We also have proposed immune indifference as a second mechanism of organ acceptance. This is supported by the fact that the organ allograft is rendered progressively less immu-nogenic by replacement of its departed migratory leukocytes by recipient cells of the same lineages (2-4). In addition, many of the donor leukocytes are ultimately disseminated to nonlymphoid sites where immune activation does not readily occur (e.g., skin and parenchymal organs) (3). Both the re-sponse (clonal activation) or nonresponse (indifference) of the immune system following transplantation are governed pri-marily by the migration and localization of the antigen (5). THOMAS STARZL 1 Department of Surgery University of Pittsburgh Medical Center Pittsburgh, Pennsylvania 15213 1 Address correspondence to: Thomas Starzl, MD, University of Pittsburgh Medical Center, Department of Surgery, 4C Falk Clinic, 3601 Fifth Avenue, Pittsburgh, PA 15213. REFERENCES 1. Bishop GA, Sun J, Sheil AG, McCaughan W. High-doselactiva-tion-associated tolerance. Transplantation 1997; 64: 1377. 2. Starzl TE, Demetris AJ, Murase N, Ildstad S, Ricordi C, Trucco M. Cell migration, chimerism, and graft acceptance. Lancet 1992; 339: 1579. 3. Starzl TE, Demetria AJ, Trucco M, et a1. Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance. Hepatology 1993; 17(6): 1127. 4. Starzl TE, Demetris AJ, Murase N, Trucco M, Thomson AW, Rao AS. The lost chord: microchimerism. Immunol Today 1996; 17: 577. 5. Starzl TE, Zinkernagel RM. Antigen localization and migration in immunity and tolerance. N Engl J Med (in press). REPLY TO "CHIMERISM AND CLONAL EXHAUSTION" We agree with Dr. Starzl that there is some concordance between our two models of transplant tolerance, although we maintain that there is a difference in the immune mechanism. In both models, donor leuk~gration to recipient tissues is central to the process, althoug~ our model it is not necessary for this to result in persistent microchimerism. Both models also predict that the outcome of the tolerance process will be deletion or inactivation of alloreactive clones of T cells. The major difference between the two models is in the im-mune events which link donor cell migration with recipient T-cell deletion or inactivation. The Pittsburgh group uses their observation of persi!'tent donor-derived microchimerism in tol-erant recipients to infer a limited graft-versus-host reaction ~ated by "donor veto/suppressor cells, cytokine pro"E:le ~hanges or enhancing antibodies" as the tolerance mechanism (1). Consequently, they have attempted to promote transplant acceptance by infusing donor bone marrow to increase the graft-d.E\rsus-host reaction and subsequent microchimerism (2). ~ur model is based on the paradoxical observation of mas-sive upregulation of interleukin-2 and interferon-")' mRNA in tile recipient lymphoid tissues of tolerant arumals (3, 4). Parallel observations in immunological models of high-dose or activation-associated tolerance have led us to propose these as mechanisms of transplant tolerance. This leads to predictions different from those of the Pittsburgh model. For instance, we predict that increasing the amount of trans-planted tissue and donor leukocytes promotes tolerance rather than rejection and that interfering with early immune activation by treating transplant recipients with some kinds of immunosuppressive drugs reduces tolerance. We have tested both these predictions and found that they are sup-ported by experimental evidence (3, 5,6). We believe that def-inition of the immune mechanism of this powerful model of transplant tolerance will come from examination of the early immune changes in recipient lymphoid tissues rather than from determining the nature of persistent microchimerism. G.A. BISHOpl,2 J. SUN3 A.G.R. SHEIL3 G.W. MCCAUGHAN! A. W. Morrow Gastroenterology and Liver Centre Centenary Institute for Cancer Medicine and Cell Biology and University of Sydney Sydney, Australia 1 A.W. Morrow Gastroenterology and Liver Centre, Centenary Institute for Cancer Medicine and Cell Biology. 2 Address correspondence to: Dr. G. Alex Bishop, A.W. Morrow Gastroenterology and Liver Centre, Centenary Institute, Locked Bag #6, Newtown NSW 2042, Australia. 3 University of Sydney. REFERENCES 1. Starzl TE, Demetris AJ, Murase N, Trucco M, Thomson AW, Rao AS. The lost chord: microchimerism and allograft survival. Immunol Today 1996; 17: 577. 2. Fontes P, Rao AS, Demetris AJ, et a1. Bone marrow augmenta· tion of donor-cell chimerism in kidney, liver, heart, and pan-creas islet transplantation. Lancet 1994; 344: 151. 3. Bishop GA, Sun J, DeCruz DJ, et al. Tolerance to rat liver allografts. m. Donor cell migration and tolerance-associated cytokine produc-tion in peripheral lymphoid tissues. J Immunol 1996; 156: 4925. 4. Bishop GA, McCaughan GW, Sun J, Sheil AGR. Microchimerism and transplant tolerance. Immunol Today 1997; 18: 455. 5. Sun J, Sheil AGR, Wang C, et a1. Tolerance to rat liver allografts IV. Tolerance depends on the quantity of donor tissue and on donor leukocytes. Transplantation 1996; 62: 1725. 6. Wang C, Sheil AGR, McCaughan GW, Bishop GA, Sun J. Effect of methylprednisolone on rat liver transplant tolerance and rejection. Immunol Cell BioI 1997; 75: AlSO. -

Chimerism and clonal exhaustion [2] (multiple letters)

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Chimerism and clonal exhaustion [2] (multiple letters)

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