Immunology and Asthma

Basic Science Research


Mission Statement:

For the past twenty-five years the Immunology group at the Pulmonary Center has focused on studying immune cell recruitment and activation in the setting of lung disease. In this work, we have been focused on the interrelationship between various chemoattractant cytokines and other factors in the selective spatial and temporal recruitment of immune cells. Information on these relationships is slowly evolving at the in vitro level, however very little is known about the application of these events in in vivo models of lung inflammation. As the various types and pathological effects of inflammation are dictated by the overall phenotype of responding cells, we will continue to ask questions addressing which existing, or new, factors are involved, and the mechanisms by which they affect overall development of inflammation.

Background:

The figure depicts the anti-inflammatory effect of IL-16 treatment in a murine model of allergic asthma. The mice were sensitized and then challenged with ovalbumin (OVA).

In 1982 Drs. Center and Cruikshank discovered the first identified T lymphocyte chemoattractant, Lymphocyte Chemoattractant Factor (LCF). In 1994 LCF was designated Interleukin-16 by the International Nomenclature Committee. IL-16 binds to CD4 on T cells and regulates their recruitment and activation. Early studies identified that increased levels of IL-16 was associated with allergen challenge of asthmatics and correlated with increased numbers of CD4+ T in the lungs. Recent animal studies using intratracheal administration of IL-16, or an IL-16-derived peptide, have demonstrated that the presence of IL-16 in the lung functions as an immunomodulator of inflammation and airway hyper-reactivity. Interestingly, this effect may be tissue specific as a number of other animal models related to autoimmune diseases, such as diabetes, Crohn’s disease, rheumatoid arthritis and multiple sclerosis, have identified that neutralization of IL-16 bioactivity results in attenuated inflammation. Current studies in our lab are designed to determine the mechanism by which IL-16 regulates inflammation in the lung. The role of IL-16 for cell recruitment, activation and differentiation of CD4+ T cells, monocytes and dendritic cells are exciting areas of interest. Preliminary data has indicated that IL-16 can selectively recruit, and induce peripheral expansion of, T regulatory cells, cells capable of suppressing inflammation, in vitro. If this observation holds true for in vivo studies, this represents a major breakthrough in the understanding of how these cells home to specific tissues, and may provide a partial mechanism for the effects of IL-16 in the lung.

IL-16 is generated by numerous cell types as a large precursor molecule that is processed prior to secretion. Recently Dr. Zhang has determined that the pro-molecule (pro-IL-16) component of IL-16 remains within the T cell, translocates into the nucleus and regulates cell cycle progression. Therefore, the second major emphasis of the laboratory relates to the functional properties of pro-IL-16 as a tumor suppressor gene. These studies use molecular techniques to dissect various portions of the precursor molecule for IL-16 to define structural correlates in the molecule with the functions. Pro-IL-16 is absent by chromosomal deletion in a number of T cell leukemias, and re-expression in vitro completely reverses the uncontrolled cell growth of these cells. Of interest, pro-IL-16 binds to the transactivating oncogene from HTLV-1 Tax, which negates the cell cycle functions of pro-IL-16. We have now defined the way it inhibits the cell cycle. It acts as a scaffolding protein that assembles a histone deacetylase complex targeted to the Skp2, which then regulates degradation of the cyclin kinase inhibitor p27kip1.

The pro-IL-16 studies are classified into two approaches, a basic science approach and a clinical relevance approach. The basic science approach is geared to delineating the mechanism by which pro-IL-16 translocates into the nucleus, forms a regulatory complex, and affects cell cycle progression. The clinical studies are based on the observations that T cells obtained from Sezary Syndrome patients, a lymphoproliferative disease, either completely lack nuclear pro-IL-16 or express very low levels. We are now investigating the correlation between lack of nuclear pro-IL-16 with disease severity. We are also designing an experimental approach whereby normal pro-IL-16 can be introduced into Sezary T cells to determine reversal of dysregulated growth.

Figure depicts deconvolution images of nuclear pro-IL-16 expression in normal T cells or in T cells obtained from Sezary Syndrome patients in either stage II or stage IV of disease. A correlation can be established for increased loss of nuclear pro-IL-16 with stage advancement.

On-going research projects:

  1. Role of IL-16 in regulation of airway inflammation in asthma
  2. Regulation of recruitment and activation of regulatory T cells in the lungs of asthmatics
  3. Regulation of T cell growth by intracellular pro-IL-16: Effects on cell-cycle related transcription factors Skp2 and p27kip1
  4. Potential role of pro-IL-16 in dysregulated growth in primary T cells from patients with Sezary Syndrome
  5. Investigation into the role of a single nucleotide polymorphism in the IL-16 promoter with IL-16 protein production and development of asthmatic inflammation.

    To learn more about the biology of IL-16 click here.

Principal Investigators:

  • David Center, M.D.
  • William Cruikshank, Ph.D.
  • Fred Little, M.D.
  • Joseph Mizgerd, Ph.D.
  • Yujun Zhang, Ph.D.
  • Jeffrey Berman, M.D.
  • Michael Ieong, M.D.
  • Ross Summer

Post-Doctoral Fellows:

  • Phil Wexler
  • Jason Konter

Selected Publications:

  1. Wilson, K., D. Cattel, Z. Wan, S. Rahangdale, F. Ren, H. Kornfeld, B. Sullivan, W. Cruikshank, and D. Center. 2005. Regulation of nuclear prointerleukin-16 and p27(Kip1) in primary human T lymphocytes. Cell Immunol.
  2. Skundric, D., R. Dai, V. Zakarian, D. Bessert, R. Skoff, W. Cruikshank, and Z. Kurjakovic. 2005. Anti-IL-16 therapy reduces CD4+ T-cell infiltration and improves paralysis and histopathology of relapsing EAE. J. Neurosci. Res. 79:680-693.
  3. Center, D., W. Cruikshank, and Y. Zhang. 2004. Nuclear pro-IL-16 regulation of T cell proliferation: p27(KIP1)-dependent G0/G1 arrest mediated by inhibition of Skp2 transcription. J Immunol. 172:1654-60.
  4. Little, F. and W. Cruikshank. 2004. Interleukin-16 and peptide derivatives as immunomodulatory therapy in allergic lung disease. Expert Opin. Biol. Ther. 4:837-846.
  5. Pritchard, J., S. Tsui, N. Horst, W. Cruikshank, and T. Smith. 2004. Synovial fibroblasts from patients with rheumatoid arthritis, like fibroblasts from Graves’ disease, express high levels of IL-16 when treated with Igs against insulin-like growth factor-1 receptor. J. Immunol. 173:3564-3569.
  6. Wilson, K., D. Center, and W. Cruikshank. 2004. The effect of interleukin-16 and its precursor on T lymphocyte activation and growth. Growth Factors, 22:97-104.
  7. Lynch, E., C. Heijens, N. Horst, D. Center, and W. Cruikshank. 2003. Cutting Edge: IL-16/CD4 preferentially induces Th1 cell migration: Requirement of CCR5. J. Immunol. 171: 4965-4968

Links: