Transfer of tolerance to collagen type v suppresses T-helper-cell-17 lymphocyte-mediated acute lung transplant rejection

Ruedi K. Braun, Melanie Molitor-Dart, Christopher Wigfield, Zhuzai Xiang, Sean B. Fain, Ewa Jankowska-Gan, Christine M. Seroogy, William J. Burlingham, David S. Wilkes, David D. Brand, Jose Torrealba, Robert B. Love

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Abstract

BACKGROUND: Rat lung allograft rejection is mediated by collagen type V (col(V)) specific T-helper-cell 17 (Th17) cells. Adoptive transfer of these cells is sufficient to induce rejection pathology in isografts, whereas tolerance to col(V) suppresses allograft rejection. Therefore, we tested whether regulatory T cells from tolerant rats could suppress the Th17-mediated rejection in the syngeneic model of lung transplantation. METHODS: Rats were subjected to syngeneic left lung transplantation, and acute rejection was induced by adoptive transfer of lymph node cells from col(V)-immunized rats. Tolerance was induced by intravenous injection of col(V), and spleen lymphocytes were used for adoptive transfer. CD4 T cells were depleted using magnetic beads. Lung isografts were analyzed using micro-positron emission tomography imaging and histochemistry. The transvivo delayed type hypersensitivity assay was used to analyze the Th17 response. RESULTS: Adoptive cotransfer of col(V)-specific effector cells with cells from col(V)-tolerized rats suppressed severe vasculitis and bronchiolitis with parenchymal inflammation, and the expression of interleukin (IL)-17 transcripts in mediastinal lymph nodes induced by effector cells alone. Analysis by transvivo delayed type hypersensitivity showed that the reactivity to col(V) was dependent on the presence of tumor necrosis factor-α and IL-17 but not interferon-γ. Depletion of CD4 T cells from the suppressor cell population abrogated the col(V)-specific protection. CONCLUSION: Th17-mediated acute rejection after lung transplantation is ameliorated by CD4 col(V)-specific regulatory T cells. The mechanism for this Th17 suppression is consistent with tolerance induction to col(V). The goal of transplantation treatment, therefore, should target Th17 development and not suppression of T-cell activation by suppressing IL-2.

Original languageEnglish (US)
Pages (from-to)1341-1348
Number of pages8
JournalTransplantation
Volume88
Issue number12
DOIs
StatePublished - Dec 1 2009

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Keywords

  • Adoptive transfer
  • Animal model
  • Autoimmunity
  • IL-17
  • Lung transplantation

ASJC Scopus subject areas

  • Transplantation

Cite this

Braun, R. K., Molitor-Dart, M., Wigfield, C., Xiang, Z., Fain, S. B., Jankowska-Gan, E., Seroogy, C. M., Burlingham, W. J., Wilkes, D. S., Brand, D. D., Torrealba, J., & Love, R. B. (2009). Transfer of tolerance to collagen type v suppresses T-helper-cell-17 lymphocyte-mediated acute lung transplant rejection. Transplantation, 88(12), 1341-1348. https://doi.org/10.1097/TP.0b013e3181bcde7b