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Kazue Takahashi, PhD

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Research summary

The innate immune system is the first line of host defense because it is instantly functional, as all innate immune molecules are present at healthy state. Recent studies have also shown that innate immunity clears dead and dying cells (that is, cell debris and apoptotic cells), suggesting a fundamental role in inflammation and its resolution and extent to maintenance of homeostasis.

My research is directed toward the understanding of innate immunity and its roles in health and disease. A critical molecules in the innate immune system is the pattern recognition molecules, including mannose-binding lectin (MBL). The human MBL gene has several polymorphisms, and low secretory haplotypes have been associated with increased susceptibility to infection, complications from diabetes, coronary artery diseases and autoimmune diseases (1, 2).

In order to investigate biological and physiologic function, we generated mice genetically lacking MBL and have crossed these mice with other strains deficient in other innate immune molecules (3). Our studies demonstrate that MBL null mice have increased susceptibility to infection (4)(5)(6), confirming clinical findings that MBL plays a key role in the isolation and elimination of pathogens. We are currently testing the effect of MBL supplementation for the treatment of influenza virus infection, and have recently initiated collaborations to include avian flu viruses in our investigations, given their threat as possible pandemic agents.

MBL appears to play a critical role in the broader host responses, including our finding that MBL null mice appear to be relatively protected from reperfusion injuries (7-10). A related finding is that MBL facilitates the removal of apoptotic cells, as we have recently demonstrated (11). The biochemical details of these processes, and the molecular details of innate immune function in the process of apoptotic cell recognition, signaling and clearance are currently poorly understood and we are working to advance understanding in all of these aspects.

More recent studies from our laboratory have focused on the involvement of MBL in wound healing. In a model of burn injury, we observed that wound healing was delayed in MBL null mice and that MBL modulates inflammatory responses both in sterile injuries as well as in infection (5, 12). These studies have provided the foundation for our future investigations into how the innate immune system functions in the regulation of inflammation and wound healing.

Finally, the aspect of our work most relevant to the clinical community is that recombinant human MBL (rhMBL) has passed a phase one clinical safety study, and a phase 2 clinical trail has just began in 2006. This accomplishment was spurred by our investigations and in vivo experimentation, taking advantage of our finding that rhMBL is physiologically equivalent to murine MBL. Additionally, we have demonstrated that rhMBL can correct MBL deficiency in murine disease models.

Our ultimate goal is to understand the mechanisms by which the innate immune system limits infection, controls inflammatory responses and maintains homeostasis. This understanding of the innate immune system will provide insights into the mechanisms of host defense against pathogens as well as in maintaining homeostasis, and is likely to open up new avenues of pharmacological intervention for treatment of autoimmune, inflammatory and infectious disease.

Selected Publications

  1. Takahashi, K., and R. A. Ezekowitz. 2005. The role of the mannose-binding lectin in innate immunity. Clin Infect Dis 41 Suppl 7:S440.
  2. Takahashi, K., W. E. Ip, I. C. Michelow, and R. A. Ezekowitz. 2006. The mannose-binding lectin: a prototypic pattern recognition molecule. Curr Opin Immunol 18:16.
  3. Takahashi, K., L. Shi, L. D. Gowda, and R. A. Ezekowitz. 2005. Relative roles of complement factor 3 and mannose-binding lectin in host defense against infection. Infect Immun 73:8188.
  4. Shi, L., K. Takahashi, J. Dundee, S. Shahroor-Karni, S. Thiel, J. C. Jensenius, F. Gad, M. R. Hamblin, K. N. Sastry, and R. A. Ezekowitz. 2004. Mannose-binding lectin-deficient mice are susceptible to infection with Staphylococcus aureus. J Exp Med 199:1379. (Takahashi is a co-first authors)
  5. Moller-Kristensen, M., W. K. Ip, L. Shi, L. D. Gowda, M. R. Hamblin, S. Thiel, J. C. Jensenius, R. A. Ezekowitz, and K. Takahashi. 2006. Deficiency of Mannose-Binding Lectin Greatly Increases Susceptibility to Postburn Infection with Pseudomonas aeruginosa. J Immunol 176:1769.
  6. Gadjeva, M., S. R. Paludan, S. Thiel, V. Slavov, M. Ruseva, K. Eriksson, G. B. Lowhagen, L. Shi, K. Takahashi, A. Ezekowitz, and J. C. Jensenius. 2004. Mannan-binding lectin modulates the response to HSV-2 infection. Clin Exp Immunol 138:304.
  7. Hart, M. L., K. A. Ceonzo, L. A. Shaffer, K. Takahashi, R. P. Rother, W. R. Reenstra, J. A. Buras, and G. L. Stahl. 2005. Gastrointestinal ischemia-reperfusion injury is lectin complement pathway dependent without involving C1q. J Immunol 174:6373.
  8. Walsh, M. C., T. Bourcier, K. Takahashi, L. Shi, M. N. Busche, R. P. Rother, S. D. Solomon, R. A. Ezekowitz, and G. L. Stahl. 2005. Mannose-binding lectin is a regulator of inflammation that accompanies myocardial ischemia and reperfusion injury. J Immunol 175:541.
  9. Moller-Kristensen, M., W. Wang, M. Ruseva, S. Thiel, S. Nielsen, K. Takahashi, L. Shi, A. Ezekowitz, J. C. Jensenius, and M. Gadjeva. 2005. Mannan-binding lectin recognizes structures on ischaemic reperfused mouse kidneys and is implicated in tissue injury. Scand J Immunol 61:426.
  10. Chan, R. K., S. I. Ibrahim, K. Takahashi, E. Kwon, M. McCormack, A. Ezekowitz, M. C. Carroll, F. D. Moore, Jr., and W. G. Austen, Jr. 2006. The Differing Roles of the Classical and Mannose-Binding Lectin Complement Pathways in the Events following Skeletal Muscle Ischemia-Reperfusion. J Immunol 177:8080.
  11. Stuart, L. M., K. Takahashi, L. Shi, J. Savill, and R. A. Ezekowitz. 2005. Mannose-binding lectin-deficient mice display defective apoptotic cell clearance but no autoimmune phenotype. J Immunol 174:3220. (Takahashi is a co-first author.)
  12. Moller-Kristensen, M., M. R. Hamblin, S. Thiel, J. C. Jensenius, and K. Takahashi. 2007. Burn Injury Reveals Altered Phenotype in Mannan-Binding Lectin-Deficient Mice. J Invest Dermatol.

Contact information

Phone: 617-726-1394
Fax: 617-714-3248
Email: ktakahashi1@partners.org