 Larry Borish, M.D.
Professor of Medicine
M.D., Boston University
lb4m@virginia.edu
Voice (434) 924-2227
Fax (434) 924-5779
1) Molecular genetic studies in allergic disease and asthma:
Dr. Borish's laboratory has described polymorphisms in the interleukin (IL)-4, IL-9, IL-10, and transforming growth factor (TGF)-ß1 promoters that link in several population studies to the presence of allergies and asthma. The IL-10 promoter polymorphism is located between sp1/sp3 and putative ets sites and influences both promoter strength and binding of sp1/sp3 complexes. IL-4 has many biological activities that support its having an important role in the pathophysiology of asthma and allergy. These include the ability of IL-4 to induce the IgE isotype switch, mediate expression of CAM-1, promote eosinophil transmigration across endothelium, stimulate mucous secretion, and induce Th2 lymphocyte differentiation, leading to release of IL-4, IL-5, IL-9, and IL-13. The IL-4 promoter polymorphism represents a C/T base exchange at 590 base pairs from the open reading frame and is associated with enhanced IL-4 promoter strength and increased binding by nuclear transcription factors to an NFAT site in the IL-4 promoter. The demonstration of functional linkages of polymorphisms in the IL-4 gene supports the concept that modulation of the biological effects of IL-4 may have a therapeutic role in asthma.
2) Immune and cellular mechanisms of rhuIL-4R:
These studies are focused on identifying the immune basis for the clinical efficacy of IL-4 antagonism. Our hypothesis is that IL-4 antagtonism will inhibit Th2-like lymphocyte differentiation, activity, and survival. Our studies demonstrate dramatic inhibition of both in vitro generated antigen-specific T cell lines and segmental allergen challenge-derived CD3+ T lymphocytes. RhuIL-4R inhibited cytokines associated with Th2-like cells (IL-5 and IL-13) while having no influence on the Th1 cytokine IFN-g. IL-4 antagonism was associated with dramatic upregulation of IL-10 and TGF-ß production in association with diminished expression of CD28 and increased expression of CTLA-4 and CD25. This inhibition was also associated with down-egulation of the anti-apoptotic protein bcl-2. Current studies are therefore focused on defining the source of IL-10 and TGF-ß, specifically whether this represents an effect of IL-4 on apoptosis of T cells or whether IL-4 antagonism promotes outgrowth of T repressor lymphocytes.
3) Immune mechanisms in chronic hyperplastic eosinophilic sinusitis (CHES):
We are investigating the role of cysteinyl leukotrienes in chronic hyperplastic eosinophilic sinusitis. We hypothesize that cysteinyl leukotrienes and other arachidonate metabolites promote fibroblast proliferation, collagen production, and secretion of proinflammatory cytokines. Cysteinyl leukotriene concentrations were significantly higher in tissue obtained from subjects with CHS as compared to healthy sinus tissue. CysLT concentrations within non-eosinophilic nasal polyps were similar to that of control tissue. 5-lipoxygenase (5-LO), 5-LO activating protein (FLAP) and leukotriene C4 synthase (LTC4S; MSGT-II) were expressed in the majority of eosinophils and subsets of mast cells, monocytes and macrophages. 5-LO and FLAP, but not LTC4S, were also expressed in neutrophils, whilst conversely epithelial cells expressed LTC4S (MSGT-II) but not 5-LO or FLAP. A C-to-A promoter polymorphism in the LTC4S gene was associated with trends towards presence of CHES and increased CysLT concentrations. CysLT1 (both mRNA and protein) receptors were expressed in the majority of eosinophils and in subsets of mast cells, monocytes, macrophages and neutrophils; CysLT2 receptors (mRNA and protein) were expressed in eosinophils, mast cells, and monocytes/macrophages. However, neither receptor is expressed on fibroblasts. Current studies emphasize the role of CysLT and other phospholipid metabolites including lysophatidic acid (LPA) and PgF2a in fibrotic pathways. These studies emphasize the importance of the CysLT synthetic and signaling pathway in the key pathological cells in CHS and provide strong rationale for the therapeutic use of CysLT modifying agents in this disease.
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Selected Publications:
Rosenwasser, LJ and Borish L. (1997). Genetics of atopy and asthma: the rationale behind promoter-based candidate gene studies (IL-4 and IL-10). Am. J. Respir. Crit. Care Med. 156 (4 Pt 2):S152-155.
Rosenwasser LJ and Borish L. (1998). Promoter polymorphisms predisposing to the development of asthma and atopy. Clin Exp Immunol. 28(Suppl 5):13-15.
Hobbs, K., J. Negri, M. Klinnert, L. J. Rosenwasser, and L. Borish. (1998). Interleukin-10 and transforming growth factor-ß promoter polymorphisms in allergies and asthma. Am J Respir Crit Care Med 158: 1958-1962.
Burchard EG, Silverman EK, Rosenwasser LJ, Borish L, et al. (1999). Association between a sequence variant in the IL-4 gene promoter and FEV1 in asthma. Am J Respir Crit Care Med 160: 919-922.
Borish L, Nelson H, Lanz M, Claussen L, Whitmore J, Agosti JM, Garrison L. (1999). Interleukin-4 receptor in moderate atopic asthma, a phase I/II randomized, placebo-controlled trial. Am J Respir Crit Care Med 160:1816-23.
Borish L, Nelson HS, Corren J, Bensch G, Busse W, Whitmore J, Agosti J. (2001). Efficacy of soluable interleukin-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol 107: 963-70.
Bensch GW, Nelson H, Borish L. (2002). Evaluation of cytokines in nasal secetions after nasal antigen challenge: lack of influence of antihistamines. An Aller Asth Immunol 88: 457-462
Steinke JW, Bradley D, Arango P, Crouse CD, Frierson H, Kountakis SE, Kraft M, Borish L. Cysteinyl leukotriene expression in chronic hyperplastic sinusitis-nasal polyposis: Importance to eosinophilia and asthma. J AllergyClin Immunol 2003; 111:342-349.
Peters EJ, Hatley, TK, Crater SE, Phillips CD, Platts-Mills TAE, and Borish L. Sinus CT scan and markers of inflammation in vocal cord dysfunction and asthma. Annals Allergy Asthma Immunol. 2003; 90:316-22.
Borish, L. Sinusitis and asthma: Entering the realm of scientific study. J Allergy Clin Immunol, 2002;109(4):606-8.
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