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

doi:10.1164/rccm.200612-1901OC

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

Joseph L Bobadilla¹, Robert B Love², Ewa Jankowska-Gan¹, Qingyong Xu¹, Lynn D Haynes¹, Ruedi K Braun², Mary S Hayney³, Alejandro Munoz del Rio¹, Keith Meyer⁴, Daniel S Greenspan⁵, Jose Torrealba⁵, Kathleen M Heidler⁶, Oscar W Cummings⁷, Takekazu Iwata⁸, David Brand⁹, Robert Presson¹⁰, William J Burlingham¹, and David S Wilkes²^*

¹ Department of Surgery, University of Wisconsin - Madison: School of Medicine and Public Health, Madison, WI, USA, ² Department of Thoracic Surgery, Loyola University, Maywood, IL, USA, ³ University of Wisconsin - Madison: School of Pharmacy, Madison, WI, USA, ⁴ Department of Medicince, University of Wisconsin - Madison: School of Medicine and Public Heatlh, Madison, WI, USA, ⁵ Department of Pathology and Laboratory Medicine, University of Wisconsin - Madison: School of Medicine and Public Health, Madison, WI, USA, ⁶ Department of Microbiology and Immunology, Indiana University School of Medicine, Center for Immunobiology, Indianapolis, IN, USA, ⁷ Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA, ⁸ Department of Thoracic Surgery, Chiba University Graduate School of Medicine, Japan, ⁹ University of Tennessee at Memphis Medical Center, Memphis, TN, USA, ¹⁰ Department of Anesthesia, Indiana University School of Medicine, Indianapolis, IN, USA

^* To whom correspondence should be addressed. E-mail: dwilkes{at}iupui.edu.

Introduction: The pathogenesis of primary graft dysfunction(PGD), a serious complication of lung transplantation, is poorlyunderstood. Human studies and rodent models have shown thatcollagen type V, col(V), stimulates IL-17-dependent cellularimmunity after lung transplantation. Our purpose was to determinewhether patients with end-stage lung disease develop pre-transplantcol(V)-specific cellular immunity, and if so, the impact ofthis response on PGD. Methods: Trans-vivo Delayed Type Hypersensitivity(TV-DTH) assays were used to evaluate memory T-cell responsesto col(V) in 55 patients awaiting lung transplantation. PaO₂/FIO₂index data was used to assess PGD. Univariate risk-factor analysiswas performed to identify variables associated with PGD. Ratsimmunized with col(V) or irrelevant antigen underwent lungisografting to determine if prior anti-col(V) immunity triggersPGD in the absence of alloreactivity. Results: We found that58.8% (10/17) of IPF, and 15.8% (6/38) of non-IPF patients testedwhile on the wait list for a lung transplant were col(V) DTH+.Col(V) reactivity was CD4⁺ T-cell and monocyte-mediated, anddependent upon IL-17, IL-1 ${beta}$ , and TNF ${alpha}$ . PaO₂/FIO₂ indices wereimpaired significantly 6-72 hrs after transplantation in col(V)-reactiveversus non-reactive patients. Univariate risk factor analysisidentified only pre-operative TV-DTH to col(V) and ischemictime as predictors of PGD. Finally, in a rat lung isograft model,col(V) sensitization resulted in significantly lower PaO₂/FIO₂,increased local TNF ${alpha}$ and IL-1 ${beta}$ production, and a moderate-to-severebronchiolitis/vasculitis when compared to control isografts. Conclusions: The data suggests that activation of innate immunity by col(V)-specificTH17 memory cells represents a novel pathway to PGD after lungtransplantation.

Key words: Lung Transplantation, Primary Graft Dysfunction, Collagen Type V, Autoimmunity, Memory T-Cell