General pulmonary diseases
Lung transplantation is the only definitive therapy for many forms of end stage lung diseases, such as cystic fibrosis, pulmonary fibrosis and COPD. However, acute rejection and chronic rejection, manifested as obliterative bronchiolitis/bronchiolitis obliterans syndrome (OB/BOS), are still impediments to the long term survival of lung transplant recipients. The incidence of acute rejection remains over 50% in the first year, and the five year graft survival is still less than 50% due primarily to the development of OB/BOS. No effective treatments prevent the onset or significantly delay the progression of OB/BOS. There is a clear need for basic science research to identify novel targets for therapy and improve outcomes. Our research uses both human and mouse models to study the immunology of allograft rejection after lung transplantation. We have a model of acute T cell mediated rejection in the lung and have found that the T cell costimulatory molecule ICOS regulates the function of T regulatory cells (CD4+Foxp3+) in the resolution of acute lung inflammation. Currently we are investigating the mechanisms by which ICOS affects the function of T regulatory cells. Furthermore, we have an ongoing collaboration with Dr. David Wilkes and his laboratory to study the T cells mediating allograft rejection and the development of obliterative bronchiolitis using a mouse model of orthotopic lung transplantation. We are also developing a lung transplant biobank using specimens collected from humans being considered for lung transplantation. We plan to use this resource to find novel pathways involved in regulating the immune response after transplantation and contributing to bronchiolitis obliterans syndrome, the major cause of allograft failure after lung transplant. In addition we are collaborating with several other institutions in the midwest to establish a consortium of lung transplant research institutions focused on researching the immunology of human lung transplantation.
Education and Training:
Clinical: Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL
Residency: Internal Medicine, University Hospitals of Cleveland, Cleveland, OH
Medical: Case Western Reserve University School of Medicine, Cleveland, OH
Critical Care Medicine
- Moore TV, Clay BS, Cannon JL, Histed A, Shilling RA, Sperling AI.
ICOS Controls T Cell Migration to the Lungs via Down-Regulation of CCR7 and CD62L.
Am J Respir Cell Mol Biol. 2011 Mar 18;.
- Hofmann Bowman MA, Heydemann A, Gawdzik J, Shilling RA, Camoretti-Mercado B.
Transgenic expression of human S100A12 induces structural airway abnormalities and limited lung inflammation in a mouse model of allergic inflammation.
Clin Exp Allergy. 2011 Jun;41(6):878-89.
- Moore TV, Clay BS, Ferreira CM, Williams JW, Rogozinska M, Cannon JL, Shilling RA, Marzo AL, Sperling AI.
Protective effector memory CD4 T cells depend on ICOS for survival.
PLoS One. 2011 Feb 18;6(2):e16529.
- Cannon JL, Mody PD, Blaine KM, Chen EJ, Nelson AD, Sayles LJ, Moore TV, Clay BS, Dulin NO, Shilling RA, Burkhardt JK, Sperling AI.
CD43 interaction with ezrin-radixin-moesin (ERM) proteins regulates T-cell trafficking and CD43 phosphorylation.
Mol Biol Cell. 2011 Apr;22(7):954-63.
- Shilling RA, Wilkes DS.
Role of Th17 cells and IL-17 in lung transplant rejection.
Semin Immunopathol. 2011 Mar;33(2):129-34.
- Benson HL, Mobashery S, Chang M, Kheradmand F, Hong JS, Smith GN, Shilling RA, Wilkes DS.
Endogenous matrix metalloproteinases 2 and 9 regulate activation of CD4+ and CD8+ T cells.
Am J Respir Cell Mol Biol. 2011 May;44(5):700-8.
- Tong J, Clay BS, Ferreira CM, Bandukwala HS, Moore TV, Blaine KM, Williams JW, Hoffman LM, Hamann KJ, Shilling RA, Weinstock JV, Sperling AI.
Fas ligand expression on T cells is sufficient to prevent prolonged airway inflammation in a murine model of asthma.
Am J Respir Cell Mol Biol. 2010 Sep;43(3):342-8.
- Shilling RA, Clay BS, Tesciuba AG, Berry EL, Lu T, Moore TV, Bandukwala HS, Tong J, Weinstock JV, Flavell RA, Horan T, Yoshinaga SK, Welcher AA, Cannon JL, Sperling AI.
CD28 and ICOS play complementary non-overlapping roles in the development of Th2 immunity in vivo.
Cell Immunol. 2009;259(2):177-84.
- Shilling RA, Wilkes DS.
Immunobiology of chronic lung allograft dysfunction: new insights from the bench and beyond.
Am J Transplant. 2009 Aug;9(8):1714-8.
- Grossman EJ, Shilling RA.
Bronchiolitis obliterans in lung transplantation: the good, the bad, and the future.
Transl Res. 2009 Apr;153(4):153-65.
- Clay BS, Shilling RA, Bandukwala HS, Moore TV, Cannon JL, Welcher AA, Weinstock JV, Sperling AI.
Inducible costimulator expression regulates the magnitude of Th2-mediated airway inflammation by regulating the number of Th2 cells.
PLoS One. 2009 Nov 4;4(11):e7525.
- Tesciuba AG, Shilling RA, Agarwal MD, Bandukwala HS, Clay BS, Moore TV, Weinstock JV, Welcher AA, Sperling AI.
ICOS costimulation expands Th2 immunity by augmenting migration of lymphocytes to draining lymph nodes.
J Immunol. 2008 Jul 15;181(2):1019-24.
- Bandukwala HS, Clay BS, Tong J, Mody PD, Cannon JL, Shilling RA, Verbeek JS, Weinstock JV, Solway J, Sperling AI.
Signaling through Fc gamma RIII is required for optimal T helper type (Th)2 responses and Th2-mediated airway inflammation.
J Exp Med. 2007 Aug 6;204(8):1875-89.
- Shilling RA, Bandukwala HS, Sperling AI.
Regulation of T:B cell interactions by the inducible costimulator molecule: does ICOS "induce" disease?
Clin Immunol. 2006 Oct;121(1):13-8.
- Tong J, Bandulwala HS, Clay BS, Anders RA, Shilling RA, Balachandran DD, Chen B, Weinstock JV, Solway J, Hamann KJ, Sperling AI.
Fas-positive T cells regulate the resolution of airway inflammation in a murine model of asthma.
J Exp Med. 2006 May 15;203(5):1173-84.
Shilling RA, Pinto JM, Decker DC, Schneider DH, Bandukwala HS, Schneider JR, Camoretti-Mercado B, Ober C, Sperling AI.
Cutting edge: polymorphisms in the ICOS promoter region are associated with allergic sensitization and Th2 cytokine production.
J Immunol. 2005 Aug 15;175(4):2061-5.