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Complement activation is not required for obliterative airway disease induced by antibodies to major histocompatibility complex class I: Implications for chronic lung rejection.
J Heart Lung Transplant. 2012 Nov; 31(11):1214-22.JH

Abstract

BACKGROUND

The role of non-complement activating antibodies (ncAbs) to mismatched donor human leukocyte antigen (HLA) in the pathogenesis of chronic lung rejection is not known. We used a murine model of obliterative airway disease (OAD) induced by Abs to major histocompatibility major histocompatibility complex (MHC) class I and serum from donor-specific Abs developed in human lung transplant (LTx) recipients to test the role of ncAbs in the development of OAD and bronchiolitis obliterans syndrome (BOS).

METHODS

Anti-MHC ncAbs were administered intrabronchially in B.10 mice or in C3 knockout (C3KO) mice. Lungs were analyzed by histopathology. Lymphocytes secreting interleukin (IL)-17, interferon-γ, or IL-10 to collagen V and K-α1 tubulin (Kα1T) were enumerated by enzyme-linked immunospot assay. Serum antibodies to collagen V and Kα1T were determined by enzyme-linked immunosorbent assay. Cytokine and growth factor expression in lungs was determined by real-time polymerase chain reaction. Donor-specific Abs from patients with BOS and control BOS-negative LTx recipients were analyzed by C1q assay.

RESULTS

Administration of ncAbs in B.10 mice or C3KO resulted in OAD lesions. There were significant increases in IL-17- and interferon-γ-secreting cells to collagen V and Kα1T, along with serum Abs to these antigens. There was also augmented expression of monocyte chemotactic protein-1, IL-6, IL-1β, vascular endothelial growth factor, transforming growth factor-β, and fibroblastic growth factor in mice administered ncAbs by Day 3. Among 5 LTx recipients with BOS, only 1 had C1q binding donor-specific Abs.

CONCLUSION

Complement activation by Abs to MHC class I is not required for development of OAD and human BOS. Therefore, anti-MHC binding to epithelial and endothelial cells can directly activate pro-fibrotic and pro-inflammatory cascades leading to immune response to self-antigens and chronic rejection.

Authors+Show Affiliations

Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22980951

Citation

Takenaka, Masashi, et al. "Complement Activation Is Not Required for Obliterative Airway Disease Induced By Antibodies to Major Histocompatibility Complex Class I: Implications for Chronic Lung Rejection." The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation, vol. 31, no. 11, 2012, pp. 1214-22.
Takenaka M, Subramanian V, Tiriveedhi V, et al. Complement activation is not required for obliterative airway disease induced by antibodies to major histocompatibility complex class I: Implications for chronic lung rejection. J Heart Lung Transplant. 2012;31(11):1214-22.
Takenaka, M., Subramanian, V., Tiriveedhi, V., Phelan, D., Hachem, R., Trulock, E., Gelman, A. E., Patterson, G. A., Hoshinaga, K., & Mohanakumar, T. (2012). Complement activation is not required for obliterative airway disease induced by antibodies to major histocompatibility complex class I: Implications for chronic lung rejection. The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation, 31(11), 1214-22. https://doi.org/10.1016/j.healun.2012.08.011
Takenaka M, et al. Complement Activation Is Not Required for Obliterative Airway Disease Induced By Antibodies to Major Histocompatibility Complex Class I: Implications for Chronic Lung Rejection. J Heart Lung Transplant. 2012;31(11):1214-22. PubMed PMID: 22980951.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Complement activation is not required for obliterative airway disease induced by antibodies to major histocompatibility complex class I: Implications for chronic lung rejection. AU - Takenaka,Masashi, AU - Subramanian,Vijay, AU - Tiriveedhi,Venkataswarup, AU - Phelan,Donna, AU - Hachem,Ramsey, AU - Trulock,Elbert, AU - Gelman,Andrew E, AU - Patterson,G Alexander, AU - Hoshinaga,Kiyotaka, AU - Mohanakumar,Thalachallour, Y1 - 2012/09/11/ PY - 2012/03/09/received PY - 2012/06/13/revised PY - 2012/08/04/accepted PY - 2012/9/18/entrez PY - 2012/9/18/pubmed PY - 2013/4/10/medline SP - 1214 EP - 22 JF - The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation JO - J. Heart Lung Transplant. VL - 31 IS - 11 N2 - BACKGROUND: The role of non-complement activating antibodies (ncAbs) to mismatched donor human leukocyte antigen (HLA) in the pathogenesis of chronic lung rejection is not known. We used a murine model of obliterative airway disease (OAD) induced by Abs to major histocompatibility major histocompatibility complex (MHC) class I and serum from donor-specific Abs developed in human lung transplant (LTx) recipients to test the role of ncAbs in the development of OAD and bronchiolitis obliterans syndrome (BOS). METHODS: Anti-MHC ncAbs were administered intrabronchially in B.10 mice or in C3 knockout (C3KO) mice. Lungs were analyzed by histopathology. Lymphocytes secreting interleukin (IL)-17, interferon-γ, or IL-10 to collagen V and K-α1 tubulin (Kα1T) were enumerated by enzyme-linked immunospot assay. Serum antibodies to collagen V and Kα1T were determined by enzyme-linked immunosorbent assay. Cytokine and growth factor expression in lungs was determined by real-time polymerase chain reaction. Donor-specific Abs from patients with BOS and control BOS-negative LTx recipients were analyzed by C1q assay. RESULTS: Administration of ncAbs in B.10 mice or C3KO resulted in OAD lesions. There were significant increases in IL-17- and interferon-γ-secreting cells to collagen V and Kα1T, along with serum Abs to these antigens. There was also augmented expression of monocyte chemotactic protein-1, IL-6, IL-1β, vascular endothelial growth factor, transforming growth factor-β, and fibroblastic growth factor in mice administered ncAbs by Day 3. Among 5 LTx recipients with BOS, only 1 had C1q binding donor-specific Abs. CONCLUSION: Complement activation by Abs to MHC class I is not required for development of OAD and human BOS. Therefore, anti-MHC binding to epithelial and endothelial cells can directly activate pro-fibrotic and pro-inflammatory cascades leading to immune response to self-antigens and chronic rejection. SN - 1557-3117 UR - https://www.unboundmedicine.com/medline/citation/22980951/Complement_activation_is_not_required_for_obliterative_airway_disease_induced_by_antibodies_to_major_histocompatibility_complex_class_I:_Implications_for_chronic_lung_rejection_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1053-2498(12)01219-3 DB - PRIME DP - Unbound Medicine ER -