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Th-17, Monokines, Collagen Type V, and Primary Graft Dysfunction in Lung Transplantation

¹ Department of Surgery, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, Wisconsin; ² Department of Thoracic Surgery, Loyola University, Maywood, Illinois; ³ School of Pharmacy, and ⁴ Department of Medicine and ⁵ Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, Wisconsin; ⁶ Department of Microbiology and Immunology, Center for Immunobiology, and ⁷ Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana; ⁸ Department of Thoracic Surgery, Chiba University Graduate School of Medicine, Japan; ⁹ University of Tennessee at Memphis Medical Center, Memphis, Tennessee; and ¹⁰ Department of Anesthesia, Indiana University School of Medicine, Indianapolis, Indiana

Correspondence and requests for reprints should be addressed to David S. Wilkes, M.D., Dr. Calvin H. English Professor of Medicine, Microbiology and Immunology, Director, Center for Immunobiology, Indiana University School of Medicine, Van Nuys Medical Sciences Building MS224, 635 Barnhill Drive, Indianapolis, IN 46202-5120. E-mail: dwilkes{at}iupui.edu

Rationale: The pathogenesis of primary graft dysfunction (PGD), a serious complication of lung transplantation, is poorly understood. Human studies and rodent models have shown that collagen type V (col[V]), stimulates IL-17–dependent cellular immunity after lung transplantation.

Objectives: To determine whether patients with end-stage lung disease develop pretransplant col(V)-specific cellular immunity, and if so, the impact of this response on PGD.

Methods: Trans-vivo delayed-type hypersensitivity (TV-DTH) assays were used to evaluate memory T-cell responses to col(V) in 55 patients awaiting lung transplantation. Pa_O2/FI_O2 index data were used to assess PGD. Univariate risk factor analysis was performed to identify variables associated with PGD. Rats immunized with col(V) or irrelevant antigen underwent lung isografting to determine if prior anti-col(V) immunity triggers PGD in the absence of alloreactivity.

Measurements and Main Results: We found that 58.8% (10/17) of patients with idiopathic pulmonary fibrosis, and 15.8% (6/38) of patients without idiopathic pulmonary fibrosis tested while on the wait list for a lung transplant were col(V) DTH positive. Col(V) reactivity was CD4⁺ T-cell and monocyte mediated, and dependent on IL-17, IL-1β, and tumor necrosis factor (TNF)-. Pa_O2/FI_O2 indices were impaired significantly 6–72 hours after transplantation in col(V)-reactive versus nonreactive patients. Univariate risk factor analysis identified only preoperative TV-DTH to col(V) and ischemic time as predictors of PGD. Finally, in a rat lung isograft model, col(V) sensitization resulted in significantly lower Pa_O2/FI_O2, increased local TNF- and IL-1β production, and a moderate-to-severe bronchiolitis/vasculitis when compared with control isografts.

Conclusions: The data suggest that activation of innate immunity by col(V)-specific Th-17 memory cells represents a novel pathway to PGD after lung transplantation.

Key Words: lung transplantation • primary graft dysfunction • collagen type V • autoimmunity • memory T cell

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Primary graft dysfunction continues to be a major barrier to successful transplantation. Despite optimal patient selection and ideal procurement techniques, primary graft dysfunction affects 11–25% of patients. What This Study Adds to the Field Activation of innate immunity by col(V)-specific Th-17 memory cells represents a novel pathway to primary graft dysfunction after lung transplantation.

 

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