Developmental Control of Integrin Expression Regulates T

Transcription

1 Developmental Control of Integrin Expression Regulates T Helper-2 Effector Homing Seung-Hyo Lee, Ph.D. Department of Medicine Pulmonary and Critical Care Division Baylor College of Medicine

2 T Helper Cell Differentiation and Host Immunity

3 Homing Molecules on T cells - Chemokines and their receptors - Cell adhesion molecules (Integrins)

4 The β2 Integrin (CD18) Family and Its Receptors CD18 (β2) CD11a (αl) CD54 CD11b (ICAM-1) (αm) CD102 CD11c (ICAM-2) (αx) CD50 CD11d (ICAM-3) (αd)

5 CD18 in Host Immunity Required for innate immunity for some bacterial pathogens Is CD18 required for adaptive immunity?

6 Summary of Previous Studies Normal in vitro T cell function without integrin CD18 Enhanced Th1 immunity without CD18 Absence or reduced Th2 function without CD18 Mechanism: Reduced Th2 but not Th1 cell homing S-H. Lee et al.. Nature Medicine, 2003

7 Question Is LFA-1 1 required for Th2 cell homing? If so, what is exact mechanism?

8 Summary Normal Th1 and Th2 development Enhanced Th1 immunity Th2 homing defect Differential integrin usage by T helper cells Th2 : integrin CD18 (LFA-1) Mechanisms of differential integrin usage Differential expression of integrins LFA-1 1 : Potential target for asthma therapy

9 An Autoimmune Basis for Smoking-Related Emphysema

10 COPD/Emphysema Chronic Obstructive Pulmonary Disease Emphysema is a major component of the morbidity and mortality of COPD Tobacco smoking is a main cause The 4th leading cause of death in the US

11 Emphysema Normal Emphysema Loss of elastic recoil by elastase Lung Hyperinflation Irreversible Reduction of Airflow

12 Summary of Previous Studies High percentage of Th1 cells in emphysema lung Induction of MMP12 and MMP9 by Th1 cytokines and chemokines MMP12 induction by CXCR3 ligand (IP-10 and MIG) Targeting CXCR3 ligands for treatment of emphysema? Grumelli et al.. PLoS Medicine

13 Purpose What is the exact mechanism of pathogenesis of emphysema? Are immune responses involved in this process? Any defect in regulation?

14 Hypothesis Emphysema is mediated through cognate immune mechanisms driven by the T helper 1 subset of T Cells

15 Rationale Emphysema can progress even quit smoking Strong Th1 immune bias in emphysema Elastin is the target of lung destruction Elastin fragments in peripheral blood Elastin fragments : Immune modulating responses in animal model

16 Experimental Approach Three study patients group (control, emphysema, asthma ) T cell responses Ab titers Regulatory T (T R ) cell responses

17 T cells Secrete IFN-γ but not IL-13 in response to Elastin Peptides S-H. Lee et al. Nature Medicine 2007

18 Blocking MHC II Attenuate T cell Responses Janeway et al. Immunobiology S-H. Lee et al.. Nature Medicine, 2007

19 CT Quantification: Assessment of Emphysema Severity 8 % 35 %

20 Cytokine vs. Disease Severity S-H. Lee et al. Nature Medicine 2007

21 Higher Detection of Anti-Elastin Ab in Plasma of Subjects with Emphysema S-H. Lee et al. Nature Medicine 2007

22 Summary of T/B cell Responses Th1 immune bias to lung elastin peptides; MHC II specific Increased Anti-elastin antibody Positively correlates with disease severity

23 Function of Lung Regulatory T (T ) cells R

24 Reduced T R cell Numbers in the Lung of Emphysema S-H. Lee et al.. Nature Medicine, 2007

25 Spontaneous Lung IL-10 Production and Lung FoxP3 mrna S-H. Lee et al.. Nature Medicine, 2007

26 Summary Robust Th1 response Higher elastin Ab titer Reduced lung T R function Emphysema : Associated with autoimmune phenotype

27 Model: Bridging Innate & Adaptive Immunity S-H. Lee et al.. Nature Medicine, 2007

28 Cigarette Consumption: Global

29 Acknowledgement David Corry, MD Corry lab members Farrah Kheradmand,, MD Kheradmand lab members Baylor College of Medicine Christie Ballantyne,, MD Wayne Smith, MD Novartis Pharma AG Gabriele Weitz-Schmidt, PhD VAMC Surgery Faisal Bakeen,, MD Joseph Huh, MD VAMC Radiology Joan Hacken,, MD icapture Centre Vancouver B.C. Harvey Coxson,, PhD

30 Clinical characteristics of the subjects used for T and B cell studies Characteristic Control Asthma Emphysema N Age (± s.d.) 58± ±14 63±10 Male LungFunction %FEV1(median± s.d.) 88±20 78±12 48±23 GOLD Stages 0-I - II-IV CT Quanti fication 2.9± ± ±10 Smoking history Never-smokers Ex-smokers Current -smokers PPY (average± s.d.) 50± ±37 Quitting time in years (average± s.d.) 15± ±10

31 Clinical characteristics of the subjects used for lung studies Charact eristic Control Emphysema N Age (±s.d.) 64±14 65 ±7 Male LungFunction %FEV1(median±s.d.) 91±15 36±25 GOLDStages 0-I II-IV Smoking history Never-smokers 3 0 Ex-smokers Current -smokers 4 4 PPY (mean±s.d.) 30±13 65±40 Quitting ime t (mean±s.d.) 25±18 10±9

32 CD4 T cell Proliferation in response to Elastin Peptides

33 Higher Elastin Reactive B cells from Lung of Emphysema Patient S-H. Lee et al. Nature Medicine In press

34 Normal T R Function in response to anti-cd3/cd28

35 Past and Future: Annual Deaths due to Tobacco (Estimated Worldwide: ) W.H.O. (The Tobacco Atlas 2006)