Hayashi, S

Iwaki, Y

Kobayashi, M

Konno, A

Noguchi, K

Ogura, K

Selby, R

Starzl, TE

Takenaka, T

Terasawa, K

Ujike, Y

Warty, V

Yagihashi, A

Yoshida, Y

English

PubMed

D-Scholarship@Pitt

Effect of FK 506 on Peripheral Blood T -Lymphocyte Subsets in Liver Transplant Patients Yagihashi, Y. Yoshida, K. Terasawa, Y. Ujike, A. Konno, K. Ogura, M. Kobayashi, T. Takenaka, Hayashi, R. Selby, V. Warty, K. Noguchi, Y. Iwaki, and T.E. Starzl LTHOUGH the detailed immunosuppressive mecha-nism of cyclosporine (CyA) differs from that of FK both CyA and FK 506 inhibit T-Iymphocyte prolifer-by blocking production of interleukin-2 (IL-2) either ltdirlectly or indirectly.I.:z Peripheral T-Iymphocyte subsets appeared to be influ-... I:ncl=a under the presence of Cy A. 3-S In rat, both CD4 and positive T lymphocytes were decreased in the periph-blood in the presence of FK 506.6 In this study, we monitored the peripheral T-Iympho-cyte subsets in orthotopic liver transplant (OL n patients ~K to evaluate the association between plasma FK 506 trough ¥ level and T-lymphocyte subsets. MATERIALS AND METHODS Patients . This study consisted of 36 randomly selected plasma samples from patients who received OLT at the Presbyterian University Hos-·.pital, University of Pittsburgh, betwccn May I, 1991 and July 31, 1991. The initial immunosuppressant was FK 506 with a low-dose OKT3, antilymphocyte globulin (ALG), and azathioprine were not used. Peripheral T-Lymphocyte Subset Monitoring Freshly isolated lymphocytes using Ficoll-Hypaque density method were stored in liquid nitrogen until the testing. .]0 0 0 1O 0 o 0 0 10 oB 0 0 0)0 o 0 8 0 ............ ............ ............. ............ ............ ............ ............ ............ 8 0 o o o o o ! 30 ... B 20 10 CD3, CD4, and CDS monoclonal antibodies (Becton Dickinson, Mountain View, Calif) were used to stain the T-lymphocyte subsets as described earlier.7 F ACSean (Becton Dickinson) was used for the analysis. Plasma FK 506 Trough Levels The FK 506 trough levels were measured using the plasma isolated from the samples monitored for the T-lymphocyte sub-sets. The plasma FK 506 trough level was determined by enzyme-linked immunosorbent assay (ELISA) described by Tamura et al.8 RESULTS FK 506 reduced the proportion of CD3 positive T lympho-cytes in the peripheral blood, however, the magnitude of reduction was not influenced by the plasma FK 506 trough level (Fig 1). The FK 506-treated patients had a decreased proportion of both CD4 and CDS T lymphocytes compared with the From the Departments of Pathology and Surgery, University of Pittsburgh School of Medicine, DeSoto at O'Hare St, Pittsburgh, Pennsylvania. Address reprint requests to Thomas E Starzl, MD, PhD. Depart-mentofSurgery, FalkCllnlc, 3601 Fifth Ave, Pittsburgh, PA 15213. ~ 1991 by Appleton & Lange 0041-13451911$3.001 +0 0 0 0 0 0 0 0 0 00 0 0 0 0 go 0 00 0 0 00 0 8 00 0 0 0 0 ll+-----------*-----~----~ .1 10 n: 506 (IIc/1III) ]0 :l:::::::::::::::::::::: ::::::::::: ::::::::::::: ::::::::::::::::::::::0: ::::::::::: :::::::::i::: ................................................. ........................ ........... ............ . ........................ ........... ............. . 20 ::::::::::::::::::::Q:: ::::::::::: ':::::::::::: . jj:~:~j~~~mjll gggjgg @jjjjmg ............................................. 10 0 0 0 0 00 0 0 .1 n: lOG (IIi/ali) 10 .1 IS 0 .1 0 10 o ,If I 0 0 0 0 0 0 0 00 8 0 0 a. 0 0 000 0 lit IK(.".) o o o 0 o o 0 o FIg 1. T-Lymphocyte subsets (COO, CD4, and COB) and CD4I 10 CD8 ratio according to the plasma FK 506 trough level. Transplantation Proceedings, Vol 23, No 6 (December), 1991: pp 2937-2938 2937 1 ;, il il i 2938 normal individuals with a few exceptions. Interestingly, the most significant suppression of CD4 or CDS proportion was observed with a FK 506 plasma trough level of 1 to 3 ng/mL. A trend of higher CD4/CDS ratio was observed as the FK 506 trough level was increased, however, it was not significant. DISCUSSION FK 506 not only inhibits early phase of CD4 positive T-Iymphocyte activation, it also suppresses CDS positive cytotoxic T-Iymphocyte generation. I •9 Our study clearly demonstrated a decreased population of both CD4 and CDS T lymphocytes. However, the most significant sup-pression was observed when FK 506 trough level was a range of I to 3 ng/mL in either subset. The suppression was inconsistent when it was more than 3 ng/mL. This result differs from the in vitro experiment that indicated the dose-dependent efficiency of FK 506.10 One possible explanation is that the in vitro study primar-ily focused on the functional study whereas our study reflects just cell popUlation. Therefore, the FK 506 trough level does not necessarily need to reflect the suppressed number of CD4 or CDS positive T lymphocytes. In fact, animal studies indicated that a higher incidence of CDS positive T cells in the spleen or thymus was observed when FK 506 was administered. 11 The time lag between the YAGIHASHI, YOSHIDA, TERASAWA ET Al monitoring results and FK 506 trough levels should not be overlooked. 11 In summary, although further T-lymphocyte studies are in order in conjunction with the subset monitoring, a rar~e of 1 to 3 ng/mL of plasma trough FK 506 levels seems te Je favorable. REFERENCES 1. Kino T, Hatanaka H, Miyata S, et al: J Antibiot (Tokyo) 40: 1256, 1987 2. Yoshimura N, Matsui S, Hamashima T, et al: Transplanta. tion 47:356, 1989 3. Hayes 1M, Valenzuela R, Novick AC, et al: Transplant Proc 19:1605, 1987 4. Chunningham p, Gross U, Matthews C, et al: Transplant Proc 19:1578, 1987 5. Tashiro M, Aikawa A, Sato I. et al: Transplant Proc 19: 1859. 1989 6. Woo J. Ross CSK. Milton II, et al: Clin Exp lmmunol 79: 109. 1990 7. Yagihashi A, Sato N. Torigoe T, et al: Cancer Res 48:27 , 1988 8. Tamura K. Kobayashi M. Hashimoto K, et al: Transplant Proc 19:23. 1987 9. Kino T, Hatanaka H, Hashimoto M. et al: 1 Antibiot (Tokyo) 40: 1249, 1987 10. Zeevi A, Eiras G. Burckart G, et al: Transplant Proc 22:60. 1990 II. Jain AB, Venkataramanan R, Cadotf E, et al: Transplant Proc 22:57. 1990 

The effect of FK 506 on peripheral blood T-lymphocyte subsets in orthotopic liver transplant patients

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The effect of FK 506 on peripheral blood T-lymphocyte subsets in orthotopic liver transplant patients

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