Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comparative Study
. 2009 Dec 27;88(12):1341-8.
doi: 10.1097/TP.0b013e3181bcde7b.

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

Ruedi K Braun  1 , 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
Affiliations
Comparative Study

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

Ruedi K Braun et al. Transplantation. .

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-alpha and IL-17 but not interferon-gamma. 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.

PubMed Disclaimer

Figures

Figure 1
Figure 1. H & E staining of lung after left lung transplantation and adoptive transfer of col(V)-specific effector and regulator T cells
A and B: 7 days after transfer of 1×107 effector cells into rats subjected to lung isograft transplantation. C and D: 7 days after adoptive transfer of 1×107 effector cells together with 4×107 regulator cells into rats subjected to lung isograft transplantation. E and F: 14 days after adoptive transfer of 1×107 effector cells together with 4×107 regulator cells into rats subjected to lung isograft transplantation. G and H: 7 days after adoptive transfer of 1×107 effector cells together with 4×107 CD4+-T-cell-depleted regulator cells. All slides are H&E stained 5 μm sections of paraformaldehyde fixed lungs.
Figure 2
Figure 2. Inflammatory response analyzed by PET 7 days after syngeneic transplanted lungs and adoptive transfer of col(V)-specific cells
(A) Transfer of 107 effector cells (Te). (B) Transfer of 107 effector cells together with 4×107 regulatory cells (Te + Tr). (C) Uninflammed normal lung. No inflammatory signals are detected in normal lungs. No transplantation has been performed in this rat.
Figure 3
Figure 3. Physiologic effects of adoptive transfer of col(V) specific effector and regulator cells
(A) Swelling of the rat ear 24 hours after injection of col(V) into the ear and adoptive transfer of Te or Te+Tr cells. HEL was used as a control antigen. (B, C) Expression of IL-17 (B) and IL-23 (C) in mediastinal lymph nodes 7 and 14 days after transplantation and adoptive transfer of LNCs and SPCs. qPCR for the cytokines IL-17 (B) and IL-23 (C). (D) FoxP3 expression in BAL and mediastinal lymph node cells from animals that obtained effector cells (Te) or effector cells (black solid and black hatched bars) and regulatory cells (Te + Tr) (gray solid and grey hatched bars). ΔΔCT with an external standard was calculated relative to cyclophilin and the fold change (2−ΔΔCT) in mRNA steady state levels between the different groups was calculated. * and ** indicates a significant difference between the data denoted (p<0.05). All values are shown as the mean of 3 to 5 independent experiments ± standard deviation.
Figure 4
Figure 4. Th17- effector response to col(V) in Col(V) sensitized mice
Inguinal lymph node cells were collected from rats immunized with col(V) (A) or control HEL (B) and were co-injected into CB17. SCID recipient footpads with PBS or sensitizing antigen. To determine the cytokines responsible for mounting a positive swelling response, cells were co-injected with sensitizing antigen and neutralizing antibodies directed against rat IFN-γ, IL-1β, TNF-α, or IL-17 and CD25 positive cells from col(V) tolerant animals. Results are shown as the 24-h net swelling response subtracting the PBS background net swelling.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Yoshida S, Haque A, Mizobuchi T, et al. Anti-Type V Collagen Lymphocytes that Express IL-17 and IL-23 Induce Rejection Pathology in Fresh and Well-Healed Lung Transplants. Am J Transplant. 2006;6:724–735. - PubMed
    1. Burlingham WJ, Love RB, Jankowska-Gan E, et al. IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants. J Clin Invest. 2007;117:3498–3506. - PMC - PubMed
    1. Yasufuku K, Heidler KM, Woods KA, et al. Prevention of bronchiolitis obliterans in rat lung allografts by type V collagen-induced oral tolerance. Transplantation. 2002;73:500–505. - PubMed
    1. Linsenmayer TF, Gibney E, Igoe F, et al. Type V collagen: molecular structure and fibrillar organization of the chicken alpha 1(V) NH2-terminal domain, a putative regulator of corneal fibrillogenesis. J Cell Biol. 1993;121:1181–1189. - PMC - PubMed
    1. Schwarze U, Atkinson M, Hoffman GG, Greenspan DS, Byers PH. Null alleles of the COL5A1 gene of type V collagen are a cause of the classical forms of Ehlers-Danlos syndrome (types I and II) Am J Hum Genet. 2000;66:1757–1765. - PMC - PubMed

Publication types