We are interested in the mechanisms by which blood-borne lymphocytes make the decision whether or not to enter a tissue while passing at high speed through the vasculature. Understanding this biological decision is crucial to our general understanding of immunosurveillance and inflammation.
Chemokines and their receptors play a key role in this decision. Differential expression of chemokines by specific tissues, and of chemokine receptors by lymphocyte subsets allow segregation of the immune system into discrete tissue-specific compartments.
Since 1998, there have been several conceptual advances in our view of chemokines and the immune system:
- The first direct experimental evidence demonstrating a role for chemokines in vascular recognition at the level of integrin-dependent adhesion triggering and arrest.
- The first examples of a role for chemokines in specialized tissue-specific lymphocyte homing and thus in defining and segregation regional immune responses.
- Implication of chemokines in the microenvironmental segregation of lymphocyte subsets within primary and secondary lymphoid organs.
These recent findings are probably only the tip of the iceberg, as the chemokine gene family continues to grow, and the roles of these chemokines continue to be elucidated. The pervasiveness of chemokines in all of these immunological events suggests that chemokines and their receptors will be fruitful targets for discovery of specific immunomodulatory drugs and treatments in the future.
The lab's main focus points are summarized as follows:
- Interactions between lymphocytes and endothelium that lead to extravasation from the blood into tissues.
- Differences between lymphocyte subsets that contribute to "tissue specific" homing.
- Involvement of chemoattractants in organization of complex micro-environments within tissues (such as tonsil, lymph node, thymus, inflammed tissues).
- Unique homing characteristics of leukemia and lymphoma cells caused by usurpation of normal homing mechanisms.
- Differences between normal and inflammed tissues that might be targetable for human therapies.
Presently, our approaches include exploration of the roles for several chemokines and their receptors in tissue-specific homing, by use of chemokine receptor knockout mice. In addition, the lab utilizes several in-vitro models of lymphocyte locomotion. These include an artificial venule system to study interaction between lymphocytes and endothelium under blood-flow conditions, and assays for dynamic adhesion and chemotaxis.
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