Project Grant R01HL173777

PATHOGENIC ROLE OF IL-39/IL-39R SIGNALING IN GRAFT-VERSUS-HOST DISEASE - ABSTRACT GRAFT-VERSUS-HOST DISEASE (GVHD) REMAINS A SIGNIFICANT SOURCE OF TRANSPLANT-RELATED MORTALITY AND MORBIDITY AFTER ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION (ALLO-HCT). INFLAMMATORY CYTOKINES PLAY AN ESSENTIAL ROLE IN T-CELL ACTIVATION AND DIFFERENTIATION TO PATHOGENIC CELLS, AND THUS PROMOTE DEVELOPMENT AND PROGRESS OF GVHD. AMONG CYTOKINES, IL-12 FAMILY ESPECIALLY IL-12 AND IL-23 HAS BEEN SHOWN TO SUBSTANTIALLY CONTRIBUTE TO THE PATHOGENESIS OF GVHD, AT LEAST PARTIALLY THROUGH PROMOTING TH1 DIFFERENTIATION AND TH17 MAINTENANCE, RESPECTIVELY. RECENTLY, IL-39 HAS BEEN PROPOSED AS A NEW ADDITION TO IL-12 CYTOKINE FAMILY THAT CONSISTS OF P19 AND EBV-INDUCED GENE 3 (EBI3). WHILE SEVERAL GROUPS PROVIDED COMPELLING EVIDENCE TO SUPPORT THE PRESENCE AND ACTIVITY OF IL-39 IN PRECLINICAL MURINE MODELS AS WELL AS IN CLINIC, OTHERS FAILED TO VALIDATE THIS NEWLY PROPOSED CYTOKINE ESPECIALLY IN HUMAN CELLS. OUR PRELIMINARY STUDY PROVIDES EVIDENCE THAT IL-39 EXISTS AND CORRELATES WITH GVHD DEVELOPMENT NOT ONLY IN PRECLINICAL MURINE MODELS BUT ALSO IN PATIENTS AFTER ALLOGENEIC HCT. HOWEVER, THE FUNCTIONAL RELEVANCE OF IL-39 HAS NOT BEEN ESTABLISHED. THE GOAL OF THIS PROPOSAL IS TO EVALUATE THE PATHOPHYSIOLOGIC RELEVANCE OF IL-39 IN GVHD DEVELOPMENT IN MICE AND HUMANS. OUR CENTRAL HYPOTHESIS IS THAT IL-39/IL-39R SIGNALING PROMOTES T-CELL ACTIVATION AND EFFECTOR FUNCTION, AND THUS PROMOTES GVHD PATHOGENESIS. THIS HYPOTHESIS WILL BE TESTED BY PURSUING TWO SPECIFIC AIMS: 1) TO VALIDATE THE ROLE OF IL-39/IL-39R SIGNALING IN GVHD AND GVL ACTIVITY IN PRECLINICAL MODELS; 2) TO DETERMINE THE FUNCTIONAL RELEVANCE OF IL-39 IN HUMANS. THE RESEARCH PROPOSED IN THIS APPLICATION IS CONSIDERED HIGHLY INNOVATIVE, BECAUSE, AS A NEWLY PROPOSED CYTOKINE, VALIDATION OF IL-39 EXISTENCE AND ACTIVITY IS URGENTLY NEEDED IN GENERAL, AND THE CURRENT STUDY IS EXPECTED TO BE THE FIRST INVESTIGATION OF IL-39 IN GVHD PATHOGENESIS. THE PROPOSED RESEARCH IS SIGNIFICANT BIOLOGICALLY AND CLINICALLY, BECAUSE IT IS EXPECTED TO VERIFY THE EXISTENCE AND BIOLOGICAL FUNCTION OF IL-39 IN MOUSE AND MAN, AND TO VALIDATE IL-39 OR ITS RECEPTOR AS A POTENTIAL BIOMARKER FOR DIAGNOSIS OR PROGNOSIS OF GVHD AS WELL AS A THERAPEUTIC TARGET IN GVHD AND BEYOND.