A.J Demetris

Demetris

M Terakura

Murase

N Ichikawa

N Murase

Q Ye

Starzl

T Sakamoto

T.E Starzl

Tashiro

Z Liu

English

PubMed

Crossref

Effects of peritransplant administration of hematopoietic growth factors on the development of chronic allograft rejection

Terakura, M

Ye, Q

Ichikawa, N

Demetris, AJ

Sakamoto, T

Liu, Z

Starzl, TE

Murase, N

D-Scholarship@Pitt

ELSEVIER Effects of Peritransplant Administration of Hematopoietic Growth Factors on the Development of Chronic Allograft Rejection M. Terakura, Q. Ye, N. Ichikawa, A.J. Demetris, T. Sakamoto, Z. Liu, T.E. Starzl, and N. Murase CHRONIC allograft rejection (CR) remains as the major obstacle to successful organ transplantation. We have previously shown that persistence of donor mul-tilineage hematolymphoid cells after transplantation corre-lates with the resistance to CR.1- 3 We hypothesized in this study that perioperative administration of hematopoietic growth factors will be able to augment donor chimerism and therefore ameliorate the development of CR. This hypoth-esis was examined using a rat heart transplantation model with simultaneous donor bone marrow (BM) infusion. METHODS Female Brown-Norway (BN, RTI n) rats received heterotopic heart grafts from male Lewis (LEW, RTll) donors. Recipients also received intravenous infusion of donor BM (2.5 x 108) harvested from the tibias and femurs on the day of transplantation and were treated with intramuscular tacrolimus (1.5 mglkg per day, Fujisawa Pharmaceutical Co., Ltd, Osaka, Japan) on days 0 to 13,20, and 27, Six groups of animals were examined using four different hemato-poietic growth factors, including rh-granulocyte colony stimulating factor (G-CSF. Amgen, Thousand Oaks, Calif), rh-granulocyte microphage colony stimulating factor (GM-CSF, Immunex, Seat-tle, Wash), rh-Flt-3 ligand (Immunex) and rh-IL-6 mutein (ImClone System Inc., Somerville, NJ) (Table 1). Levels of chimer-ism were semiquantitatively analyzed by polymerase chain reaction and Southern hybridization using rat sex determining region-Y (SRY) specific oligonucleotide primers4 in sequential blood sam-ples and recipient tissues at sacrifice on day 100 after transplanta-tion. Heart allografts were further histopathologically analyzed for the severity of CR. RESULTS Donor BM infusion alone significantly increased male DNA concentration in the blood for the first 2 months after grafting. Additional treatment with growth factors did not show further significant augmentation of blood chimerism. At day 100, donor male DNA was not detected in the peripheral blood of any recipient, but it was found more frequently in recipient tissues such as the skin, native heart, and spleen. Level and frequency of chimerism were signif-icantly increased in recipients with adjunctive BM infusion and further augmented by Flt-3 ligand and IL-6 treatment (Table 1). Histopathologic analysis of heart allografts at day 100 revealed the significant amelioration of overall inflam-mation in BM-infused recipients compared to uninfused controls (Table 1). Evaluation of arterial changes demon-strated the significant improvement of the degree of oblit-erative arteriopathy in BM-infused recipients treated with G-CSF and IL-6 (Table 1). Additionally, when samples from all cardiac allografts of six groups were pooled and the histopathologic changes were correlated with the pooled From the Thomas E. Starzl Transplantation Institute, Depart-ments of Surgery and Pathology, University of Pittsburgh, Pitts-burgh, Pennsylvania. Supported by Project Grants OK 29961 and AI/DK038899-01A2 from the National Institutes of Health, Bethesda, Maryland. Address reprint requests to Dr M. Terakura, University of Pittsburgh, TE Starzl Transplantation Institute, E1540 Biomedi-cal Science Tower, Pittsburgh, PA 15261. Table 1. Effects of Adjunctive Donor Bone Marrow Infusion and Perioperative Administration of Hematopoietic Growth Factors on Levels of Chimerism and Histopathologic Changes of Chronic Allograft Rejection Group Transplantation Growth Factor Dose (kg/d) HTX None NA 2 HTX + 8M None NA 3 HTX + 8M G-CSF 200/Lg 4 HTX + 8M GM-CSF 200 /Lg 5 HTX + 8M Flt-3 ligand 200 /Lg 6 HTX + 8M IL-6 500/Lg All values are mean :!: SE. 'In native heart at 100 days after transplantation. P values vs HTX (group 1): t <.001; * <.0001; vs HTX + BM (group 2): ~ <.05. Abbreviation: OA: obliterative arteriopathy. 0041-1345/99/$-see front matter PH S0041-1345(98)01810-7 870 n 7 8 5 5 6 6 Inflammation Chimerism' OAgrade Score (X10·3%) 0.94:!: 0.33 2.71 :!: 0.36 0.69:!: 0.42 0.98 :!: 0.14 1.38 :!: 0.26t 21.8 :!: 9.22t 0.38:!: MKM9~ 0.63 :!: 0.13* 116 :!: 39.8* 0.48 :!: 0.14 0.94:!: 0.37* 19.2 :!: 9.79t 0.57 :!: 0.10 0.75 :!: 0.11* 109 :!: 4MKR*~ 0.44 :!: MK1M~ 0.92 :!: 0.24* 87.7 :!: PMKR*~ © 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 31, 87D-871 (1999) PERITRANSPLANT OF HEMATOPOIETIC GROwrH FACTORS levels of chimerism in the native hearts of these same animals, significant inverse correlation was found between the severity of CR (inflammation score and arterial changes) and levels of chimerism. DISCUSSION It was determined in this study whether there was a correlation between the quantity and localization of chimer-ism and severity of CR using histopathologic endpoints and PCR analysis of Y -chromosome in sex-mismatched trans-plantation. Results demonstrate that CR was reduced in inverse proportion to the amount of detectable chimerism, whieh in turn was greater in animals given adjunct BM and postoperative growth factor therapy. Differences among growth factors in increasing chimerism and preventing CR were not significant, but chimerism tended to be greater with Flt-3 ligand and IL-6. Trends of reduced CR were seen with G-CSF and IL-6 treatment. G-CSF and GM-CSF already have been widely used in clinical bone marrow 871 transplant recipients and after cancer chemotherapy. The administration of G-CSF and GM-CSF long after trans-plantation to stable organ recipients has not increased the risk of either rejection of GVHD. This study demonstrates that pcrioperative hematopoietic growth factor treatment is effective in enhancing the level of chimerism and improving histopathologic abnormalities associated with CR. Preclin-ical laboratory studies under controlled circumstances will be doubly important to further improve the method to use growth factors for CR. REFERENCES 1. Murase N, Starzl TE, Tanabe M, et al: Transplantation 60:158, 1995 2. Dcmetris AJ, Murase N. Ye Q, et al: Am J Pathol 150:563, 1997 3. Starzl TE, Demetris AJ. Murase N, et al: Immunol Today 17:577, 1996 4. Tashiro H, Fukuda Y, Kimura A, et al: Transplantation 58:745, 1994 

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Effects of peritransplant administration of hematopoietic growth factors on the development of chronic allograft rejection

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