B cell phenotypes in baboons with pig artery patch grafts receiving conventional immunosuppressive therapy

Takayuki Yamamoto, Qi Li, Hidetaka Hara, Liaoran Wang, Hongmin Zhou, Juan Li, Devin E. Eckhoff, A. Joseph Tector, Edwin C. Klein, Ray Lovingood, Mohamed Ezzelarab, David Ayares, Yi Wang, David K.C. Cooper, Hayato Iwase

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Background: In the pig-to-baboon artery patch model with no immunosuppressive therapy, a graft from an α1,3-galactosyltransferase gene-knockout (GTKO) pig elicits a significant anti-nonGal IgG response, indicating sensitization to the graft. A costimulation blockade-based regimen, e.g., anti-CD154mAb or anti-CD40mAb, prevents sensitization. However, neither of these agents is currently FDA-approved. The aim of the present study was to determine the efficacy of FDA-approved agents on the T and B cell responses. Methods: Artery patch xenotransplantation in baboons was carried out using GTKO/CD46 pigs with (n = 2) or without (n = 1) the mutant transgene for CIITA-knockdown. Immunosuppressive therapy consisted of induction with ATG and anti-CD20mAb, and maintenance with different combinations of CTLA4-Ig, tacrolimus, and rapamycin. In addition, all 3 baboons received daily corticosteroids, the IL-6R blocker, tocilizumab, at regular intervals, and the TNF-α blocker, etanercept, for the first 2 weeks. Recipient blood was monitored for anti-nonGal antibody levels by flow cytometry (using GTKO/CD46 pig aortic endothelial cells), and mixed lymphocyte reaction (MLR). CD22 + B cell profiles (naïve [IgD + /CD27 ], non-switched memory [IgD + /CD27 + ], and switched memory [IgD /CD27 + ] B cell subsets) were measured by flow cytometry. At 6 months, the baboons were euthanized and the grafts were examined histologically. Results: No elicited anti-pig antibodies developed in any baboon. The frequency of naïve memory B cells increased significantly (from 34% to 90%, p = 0.0015), but there was a significant decrease in switched memory B cells (from 17% to 0.5%, p = 0.015). MLR showed no increase in the proliferative T cell response in those baboons that had received CTLA4-Ig (n = 2). Histological examination showed few or no features of rejection in any graft. Conclusions: The data suggest that immunosuppressive therapy with only FDA-approved agents may be adequate to prevent an adaptive immune response to a genetically-engineered pig graft, particularly if CTLA4-Ig is included in the regimen, in part because the development of donor-specific memory B cells is inhibited.

Original languageEnglish (US)
Pages (from-to)12-20
Number of pages9
JournalTransplant Immunology
Volume51
DOIs
StatePublished - Dec 2018
Externally publishedYes

Keywords

  • Artery patch
  • CTLA4-Ig
  • FDA-approved agents
  • Pig
  • Rapamycin
  • Tacrolimus
  • Xenotransplantation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Transplantation

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