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Functional Th1 Cells Are Required for Surgical Adhesion Formation in a Murine Model¹

Arthur O. Tzianabos^2,*, Matthew A. Holsti^2,*, Xin-Xiao Zheng, Arthur F. Stucchi, Vijay K. Kuchroo, Terry B. Strom, Laurie H. Glimcher^|| and William W. Cruikshank^3,¶

^* Department of Medicine and Channing Laboratory and Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; Division of Immunology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115; Department of Surgery, Boston University Medical Center and ^¶ Pulmonary Center, Boston University School of Medicine, Boston, MA 02118; and ^|| Harvard School of Public Health and Harvard Medical School, Boston, MA 02115

Tissue trauma in the peritoneal and pelvic cavities following surgery or bacterial infection results in adhesions that are a debilitating cause of intestinal obstruction, chronic pelvic pain, and infertility in women. We recently demonstrated that CD4⁺ β T cells are essential for development of this process. Using a murine model of experimental adhesion formation, we now demonstrate that adhesion formation is characterized by the selective recruitment of Tim-3⁺, CCR5⁺, CXCR3⁺, IFN-⁺ cells, indicating the presence of a Th1 phenotype. We further demonstrate that adhesion formation is critically dependent on the function of Th1 cells because mice genetically deficient for IFN-, T-bet, or treated with Abs to the Th1-selective chemoattractant IL-16 show significantly less adhesion formation than wild-type mice. In addition, disrupting the interaction of the Th1-specific regulatory molecule Tim-3, with its ligand, significantly exacerbates adhesion formation. This enhanced response is associated with increases in the level of neutrophil-attracting chemokines KC and MIP-2, known to play a role in adhesiogenesis. These data demonstrate that the CD4⁺ T cells orchestrating adhesion formation are of the Th1 phenotype and delineate the central role of T-bet, Tim-3, IFN-, and IL-16 in mediating this pathogenic tissue response.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by research grants from the National Institutes of Health (RM64805-01, HL32802, and CA112663 to L.H.G.).

² A.O.T. and M.A.H. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. William Cruikshank, Boston University School of Medicine Pulmonary Center, R-304, 715 Albany Street, Boston, MA 02118. E-mail address: bcruiksh{at}bu.edu

⁴ Abbreviations used in this paper; LN, lymph node; WT, wild type.