Transfer of tolerance to collagen type V suppresses T-helper-cell-17 lymphocyte-mediated acute lung transplant rejection.
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-alpha and IL-17 but not interferon-gamma. Depletion of CD4+ T cells from the suppressor cell population abrogated the col(V)-specific protection.


CONCLUSIONS
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.
Braun
Ruedi K
RK
Department of Thoracic and Cardiovascular Surgery, Loyola University, Maywood, IL 60153, USA. rubraun@lumc.edu
Molitor-Dart
Melanie
M
Wigfield
Christopher
C
Xiang
Zhuzai
Z
Fain
Sean B
SB
Jankowska-Gan
Ewa
E
Seroogy
Christine M
CM
Burlingham
William J
WJ
Wilkes
David S
DS
Brand
David D
DD
Torrealba
Jose
J
Love
Robert B
RB
D000208:Acute Disease; D000818:Animals; D024062:Collagen Type V / Q000276:immunology*; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000175:diagnosis / Q000276:immunology*; D007111:Immunity, Cellular; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology*; D016040:Lung Transplantation / Q000276:immunology*; D049268:Positron-Emission Tomography; D051381:Rats; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014184:Transplantation, Homologous
D024062:Collagen Type V; D020381:Interleukin-17