We have reported that, a short delayed course of intramuscular FK 506 can induce a,donor strain-specific immunologic unresponsiveness to cardiac allograft in rats.1 Further studies have been performed to determine if this agent can induce graft acceptance after canine renal (KT) or hepatic (OLT) allotransplantation. Preliminary descriptions of these efforts have been published.

Eiras, G

Furukawa, H

Imventarza, O

Oguma, S

Oks, A

Starzl, TE

Todo, S

Ueda, Y

Wu, YM

Zeevi, A

English

PubMed

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(DO Induction of Graft Acceptance After Dog Kidney or Liver Transplantation Y. Ueda. S. Todo. G. Eiras. H. Furukawa. O. Imventarza. Y.M. Wu. A. Oks. A. Zeevi. S. Oguma, and T.E. Starzl WE have reponed that a short delayed course of intramuscular FK 506 can induce a donor strain-specific immunologK unresponsiveness to cardiac allograft in rats. 1 Further studies have been performed to determine if this agent can induce graft acceptance after canine renal (KT) or hepatic (OL T) allotransplantation. Preliminary descriptions of these efforts have been publishedK~ MATERIALS AND METHODS Animals and Transplant Procedures Female beagle dogs were used for recipients. The donors were mongrel dogs. exce~t for groups 2 and 4 in the OlT trials. in which a beagle to t-eagle combination was used. Kidney grafts were implanted int0 the right iliac fossa and livers implanted were into the orthotopl': position using a previously described technique .' Drug Administration FK 506 for intramu>.:ular IJse "as supplied by the Fujlsa\\oa Pharma-ceutical Co. Ltd. l~KKikaK Japan. This powder was di"ol\ed in saline. To pre\'ent yomitirK~ ,;:aused ~I FK 5D6. 2.0 mgkg oi :1tropine sulfate was given intmmu;.:ularl, t'-'Ice per day for I \\eek. Experimental Designs The protocols are ,ummarized In Table I for ren,,! rransplantalilln and in qa~le 2 for Jt\'cr transplantation. :\n FK ~lh bolus at a do,e of 1.0 mglkgd '-' as gi\en as rescue pulse therapy if rejection occurred. FK 506 was never given beyond 90 days after ~urgeryK Biochemistry Blood samples were taken at 3-day intervals for measurements of serum creatinine, total bilirubin. SGOT. SG PT. glucose. and amylase. Mixed Lymphocyte Reaction About 10 ml of l:>lood was drawn every 2 weeks from chronically surviving recipients for mixed lymphocyte reaction (MLR) studies.· TheIr peripheral lymphocytes were cocultured with From the Departments of Surgery and Pathology. University Health Center of Pmsburgh. University of Pittsburgh, PA; the Department of PathOlogy. St Mary's Hospital and Medical School. London, Englard: and the Veterans Administration Medical Cen· ter, Pittsburgh. PA. Supported ::y research grants from the Veterans Administration and PrOject Grant No. OK 29961 from the ~ational Institutes of Health. Bethesca. MD. Address reonnt requests.to Thomas E. Starzl. MD, PhD. De· partment of Surge')'. 3601 Fiflh Avenue. Fak CliniC. Pittsburgh, PA 15213. c 1990 by Apoiel:m & Lange 0041·134590 S3 00 -0 Table 1. Prolongation of Renal Allograft Survival in Dogs ·_··;""""'ilisc .... :a' POStO:-e'2: ,e Days "K 506 M~ ~" 3':'6 Grauo -'9 <g d! Ac ..... I~ s:'a;ion 0 0 2 0.5 45.6 3 10 4.5.6 4 2.0 4.5.6 5 5.0 45.6 6 10.0 45.6 7 50 5 8 100 5 9 250 5 10 05 45. 6 ai~s every 2 weeks 11 1.0 4.5.6 plt.s every 2 weeks • Ge'""erahze-: ,',':iCOXO" 1esl - Dc:·:s dlec '-: ~ jntt..ssusceotlon With low serum c'ea.:"1fne level : DC.;:s Olec ":--, emaCiatIon WIth low serum creat~"""De ·eve! n 6 4 4 6 6 6 6 6 4 2 4 ~ ... -, .2: -: -e.c e ~ 12 14.17. 18 20 21 22 33 31 .)6. 66 67 6 ' 20 ' 2' ' .)3. 54. 125 ., - • S' 26 ' 60. 60 79 ·2C 31 55.' 68. 75 ; ~ '0 - 20. 23. 25.53 7 - 8. 1 e. 11. 41. 58 6.' 11.- 12.' 96 127. 129 2.).' 26.' 113 132 fK~ :::=:r, '3 2.! 525 .!52 .)23 .)3.3 25.2 225 313 128 738 o CO: 000: 002 001:; '.0013 ·,0015 NS NS 80 Transplantation Proceecl(Igs. Vol 22. No 1. Suppl 1 i "'ebruaryl. 1990 00 8e-32 s ~ s 3 • 5 J·82 GRAFT ACCEPTANCE AFTER DOG hfa~bv OR LIVER Tx 81 Table 2. Prolongation of Hepatic Allograft Survival In Dogs Intramuscular PostOpe'3:-ve Days FK 506 of Fo( 506 Group (mg'kgd) Adm,r'scatlon n 1 (M.8) 0 c 6 2 (8/B) 0 C 6 3 (Mi8) 4.5. 6 7 4 (BIB) 4.5. 6 8 • Generalized Wilcoxon test. t Dogs died Irom intussusception without Signs of re::-::tlOn donor spleen cells or spleen cells of third-party donors, as described in a previous report. 4 Histology When animals died or were killed. autopsy '''.is performed imme-diately. Tissues were fixed with 1O'7c formalin and stained with hematoxylin and eosin. Statistics The Student's 1 test and generalized WilcoxL'n test were applied for the statistical analysis of group means. A rr0bability of <0.05 was considered to be significant. RESULTS :\5 seen in Tables 1 and 2. significant prolongation of renal or hepatic graft survival could be obkined by FK 506 treatment, \\hen compared with nontreared Jnimals. Two OL T dogs survived over 600 Jays after <urgery. and one of these IS still alive in good condillon at 1:-:0 postoperative days. suggesting tolerance Induction b~ FK 506 delayed treatment was achieved. In KT recipient;. there were no permanent survivors. in spite of the fact ::-::Jt the rejection-free period W,,h prolunged. in propurtion [,' Increases in the FK ~MS Intramu.,cular dosage IFig I). F,'ur of six dogs treated by tntermitknt FK '1)6 admtniD!~ "tiLln Igruup, 10 and II) suniled for 11~K 127. 12':1. and 1K~O day,. respec-tile/I. FK ,'On re.,(ue tre:ltment cuul..! -e\er'ie :-:orD~ of ongulng re.lectilln epi"lde., In renal .l .. ID~raftI I Fi.[: 21. '" ~-c 0 e:o v '" 0 0 0 0 e ~ v cr: .. 'i2 ci: 0.00.1-5-5 F( : M Dosage mg kg :2. N .... r'.ce· o~ Dogs ,I , I I ( , ~ i p 00 5 Fig 1. Re,eclion·lree pe'lod In canine rena ~ otransplantatlon treated by dose·dependent. delayed Intramuse a' administration of FK 506. Survival Time (d) 7, 8, 19. 26, 41 7,7,8.13,35,38 9,t 16,24,28,360, >620,630 21,126,34,58,60,62,75,193 Mean P Value' 18.2 180 2410 <0.05 66.1 <0.01 unless the serum creallnme levels were higher than 5.0 mg/dl. As the intramuscular dosage of FK 506 was in-creased to more than 2.0 mg/kg/d. more of the dogs died from intussusception or emaciation. with well-functioning kidney grafts (Table I). The MLR responses were remarkably suppressed, at least for the first month after initial FK 506 delayed treatment. in both renal and hepatic recipients. As shown in Fig 3. the MLR inhibition of reactivity against donor spleen cells at the lIth postoperative week was stronger • 100 =0 C ....... Ol E <1> C :5 <i 50 " U :; OJ VJ Re\lersed Rejection Non- Re\lersec Rejection • • • ::; • • >< • >< -C : " • ' 50 POD 4-5-6 • .. • ::; C ~ ~ FK I. M Dosage ;mg kg 'day.: 0 Fig 2. Outcomes of the FK 506 rescue treatment on the first rejection epiSOde In canine renal allograft, , 10 ~ 60 E ..... 50 '" = MLR tc T~Irc :::lar~I U 40 ~ 0. 30 :::J ~ 20 ] ;. r. to ..... .I 901 903 907 908 Dog Number Fig 3. Comparison of MLR responses agalrst doror and third· party spleen cells at the 11 th postoperative week. The potency of responses were evaluated by 3H-thymldlne uptake. 82 than that against third-party spleen cells. indicating that donor-specific immunosuppression was induced by FK 506 delayed and intermittent treatment. DISCUSSION As described in a previous report,1 a 3-day course of intramuscular FK 506 at 1.0 mg/kg/d was the best dose for optimal graft protection without serious toxic side effects in dogs. For both rescue and intermittent FK 506 treat-ment. even less than 1.0 mg might be sufficient to reverse ongoing or recurrent rejection. The mechanisms of FK 506-induced long-term allograft acceptance have been investigated by Murase et all and Ochiai et al. 5 These investigators concluded that there was specific immunologic unresponsiveness against the donor as a result of delayed treatment in rats with FK 506. Although we could not achieve permanent graft accep-tance after renal allotransplantation in dogs. the MLR UEOA. TOOO. EIRAS ET AL study showed that antigen recognition was ~pecitlcall:­reduced by recipient treatment. whether gi'.en transiently or repeatedly. Why unresponsiveness was eaSier to induce with livers than with kidneys is not presently known. it is already known that FK 506-related to\icity is most prominent in dogs. ~KS This species peculiarity apparently is not relevant to the human situation. 7 REFERENCES I. Murase :-J. T udo S. Lee PH. et al: Transplant Proc 19: 71. 1987 I suppl 6) 2. Todo S. Ueda Y. Demetris 1A. et al: purger~ 104:239. 1988 3. Todo S. Kam l. Lynch S. et al: Semin Liver Dis 5:309.1985 4. Eiras G. Zeevi A. Todo S. et al: Immunoblology 110 press) 5. Ochiai T. Nakajima K. :-<agata M. et al: Transplantation 44:734. 1987 6. Collier Sl. Caine R. Thiru S. et al: Transplant Proc 20: :26. 1988 7. Starzl TE. Todo S. Fung J. et al: Lancet 1:1000. 1989 

Induction of graft acceptance after dog kidney or liver transplantation

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Induction of graft acceptance after dog kidney or liver transplantation

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