The broad, long-term objectives of this laboratory are to understand the mechanisms by which CD4+ T cells mediate allergic lung disease. Specifically, this proposal will define the role of adhesion molecules in regulating the homing of T helper type 1 (Th1) and Th2 cells in an allergic asthma model. Only Th2 cells mediate allergic lung disease, but defining the adhesion molecules that differentially regulate Th1 and Th2 homing provides an opportunity to selectively exclude subsets implicated in disease. Homing is defined here as the ability of effector CD4+ T cells to exit the vascular space and enter parenchymal tissues and will be assessed by comparing numbers of cells present in spleens (where they originate) and the lung (where they immigrate). We hypothesize that integrins and their receptors are differentially required by Th1 and Th2 cells for homing to lung. To prove this, we have begun to explore the role of CD18 (integrin a2) and CD11 a (integrin DL), the heterodimeric partner of T cell-expressed CD18 (forming leukocyte function antigen 1;LFA-1), and related integrin family members in a Th2-dependent model of allergic lung disease. CD18- deficient mice generate functional Th1 and Th2 cells following intranasal allergen challenge but fail to develop asthma- like allergic disease as seen in wild type control mice. Th2, but not Th1, cells remained confined to the spleens of CD18-/- mice and were unable to home to lung. Together, our data indicate that CD18 coordinates the homing of Th2, but not Th1, cells to lung, revealing a new paradigm in which T helper effector subsets differentially depend on integrins for tissue homing.
Specific Aim 1 will explore the role of two molecular partners of CD18, CD11a and CD11 b in T cell effector development and homing using gene deficient mice in the same asthma model.
Specific Aim 2 will examine the requirement of the LFA-1-CD54 (intercellular adhesion molecule 1;ICAM-1) interaction in differentially coordinating lung Th1 and Th2 homing using gene deficient mice and a novel LFA-1 inhibitor with potential clinical applicability. Finally, Specific Aim 3 will determine the basis for the selective requirement of LFA-1 for Th2 homing using an in vitro chemotaxis model of homing. The work proposed will provide mechanistic insight into the pathogenesis of allergic lung disease and provide a rational basis for development of integrin-based therapeutics for interrupting Th2-driven allergic processes.
| Millien, Valentine Ongeri; Lu, Wen; Mak, Garbo et al. (2014) Airway fibrinogenolysis and the initiation of allergic inflammation. Ann Am Thorac Soc 11 Suppl 5:S277-83 |
| Knight, John M; Lee, Seung-Hyo; Roberts, Luz et al. (2014) CD11a polymorphisms regulate TH2 cell homing and TH2-related disease. J Allergy Clin Immunol 133:189-97.e1-8 |
| Millien, Valentine Ongeri; Lu, Wen; Shaw, Joanne et al. (2013) Cleavage of fibrinogen by proteinases elicits allergic responses through Toll-like receptor 4. Science 341:792-6 |
| Shearer, William T; Corry, David B (2012) High prevalence of asthma in HIV-infected adults: new insights. J Allergy Clin Immunol 129:715-6 |
| Yang, Tianshu; Ramocki, Melissa B; Neul, Jeffrey L et al. (2012) Overexpression of methyl-CpG binding protein 2 impairs T(H)1 responses. Sci Transl Med 4:163ra158 |
| Grünig, Gabriele; Corry, David B; Reibman, Joan et al. (2012) Interleukin 13 and the evolution of asthma therapy. Am J Clin Exp Immunol 1:20-27 |
| Porter, Paul; Polikepahad, Sumanth; Qian, Yuping et al. (2011) Respiratory tract allergic disease and atopy: experimental evidence for a fungal infectious etiology. Med Mycol 49 Suppl 1:S158-63 |
| Porter, Paul C; Yang, Tianshu; Luong, Amber et al. (2011) Proteinases as molecular adjuvants in allergic airway disease. Biochim Biophys Acta 1810:1059-65 |
| Hong, Jeong-Soo; Greenlee, Kendra J; Pitchumani, Ramanan et al. (2011) Dual protective mechanisms of matrix metalloproteinases 2 and 9 in immune defense against Streptococcus pneumoniae. J Immunol 186:6427-36 |
| Tai, W; Roberts, L; Seryshev, A et al. (2011) Multistrain influenza protection induced by a nanoparticulate mucosal immunotherapeutic. Mucosal Immunol 4:197-207 |
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