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Successful islet allotransplantation in diabetic rats immunosuppressed with FK506: A functional and immunological study

Tze, WJ and Tai, J and Cheung, SSC and Murase, N and Starzl, TE (1994) Successful islet allotransplantation in diabetic rats immunosuppressed with FK506: A functional and immunological study. Metabolism, 43 (2). 135 - 139. ISSN 0026-0495

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Abstract

The effect of a novel immunosuppressive agent, FK506, on fresh islet allografts was evaluated in diabetic rats across major histocompatibility complex (MHC) barriers with respect to the transplantation (TR) site, islet source, treatment regimen, and antidonor antibody (Ab) titers of the recipients after TR. The functional periods of Wistar (Wi) islets transplanted under kidney capsule (KC) or intraportally (IPo) and of a mixture of Wi and Lewis (Le) islets under KC or IPo in nonimmunosuppressed ACI rat recipients were 6.9 ± 0.4 (n = 7), 6.4 ± 0.5 (n = 7), 5.6 ± 0.4 (n = 7), and 6.2 ± 0.4 (n = 5) days, respectively. FK506 treatment at 1 mg/kg/d intramuscularly (IM) for 2 weeks (protocol I) following islet TR under KC and IPo significantly prolonged the allograft function to more than 71.8 ± 11.3 (n = 10) and 161.7 ± 18.6 (n = 11) days, respectively. Additional treatment with FK506 at 1 mg/kg/wk (protocol II) further increased the islet survival under KC to more than 212.6 ± 22.3 (n = 8) days. With this FK506 treatment protocol, the Wi + Le mixed-islet allograft function was extended to more than 106.1 ± 10.5 (n = 7) and 167.9 ± 28.6 (n = 7) days under KC and IPo, respectively. Nephrectomy in 8 8 ACI rats with long-term-functioning Wi (n = 6) and Wi + Le (n = 2) islet allografts resulted in their return to hyperglycemia. Immunohistochemical staining showed abundant insulin-positive cells at the graft site, with small numbers of CD4- and CD8-positive cells present in the vicinity of the normal-appearing islets. Macrophages were not detected. The immunosuppressive effect of FK506 was further tested in ACI rats presensitized by a previous Wi islet TR. When the duration between the first and second TR under KC was 114.3 ± 20.5 days, protocol II treatment significantly prolonged the graft function to more than 152.9 ± 28.7 (n = 8) days. However, with a short duration of about 2 weeks between the two TRs, the same FK506 protocol achieved islet graft function of 14.0 ± 3.8 days (n = 7). Additional immunosuppression with cyclophosphamide did not further improve the survival time. Antidonor Abs detected in ACI recipients of Wi islet allografts were significantly lower in the FK506-treated animals compared with the nontreatment group. Wi and Le skin grafts performed in three ACI rats with long-term-functioning Wi islets IPo caused the rejection of the islet allografts. Skin grafts were also rejected in the first-set fashion. Six ACI recipients with long-term-functioning IPo Wi islet allografts were rendered hyperglycemic by streptozocin (STZ) injection. Long-term normoglycemia without further FK506 immunosuppression was achieved following retransplantation with fresh Wi islets IPo (n = 2), but not under KC (n = 2). The results of the present study indicate that FK506 was an effective immunosuppressant for islet allotransplantation in diabetic ACI rats across MHC barriers with islets from two donor strains, as well as in sensitized recipients whose antidonor activities had subsided. The efficacy of the immunosuppression was influenced by the FK506 treatment protocol and the site of the islet transplant. The results suggest that FK506 could be useful in clinical islet TR. © 1994.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Tze, WJ
Tai, J
Cheung, SSC
Murase, N
Starzl, TEtes11@pitt.eduTES11
Centers: Other Centers, Institutes, or Units > Thomas E. Starzl Transplantation Institute
Date: 1 January 1994
Date Type: Publication
Journal or Publication Title: Metabolism
Volume: 43
Number: 2
Page Range: 135 - 139
DOI or Unique Handle: 10.1016/0026-0495(94)90234-8
Institution: University of Pittsburgh
Refereed: Yes
ISSN: 0026-0495
Other ID: uls-drl:31735062112044, Starzl CV No. 1410
Date Deposited: 08 Apr 2010 17:23
Last Modified: 13 Oct 2017 20:55
URI: http://d-scholarship.pitt.edu/id/eprint/4796

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