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Dr.
Thomas E. Lane
Ph.D., University of California, Los Angeles,1993
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Work in my laboratory at the University
of California, Irvine has focused on understanding the molecular and cellular
mechanisms involved in regulating inflammation following microbial infection.
Specifically, we are interested in evaluating the functional contributions of
chemokines (chemotactic chemokines) and their receptors in the initiation and
maintenance of inflammation following infection. Current work is divided into
three major research areas: i) utilize a mouse model of viral-induced encephalomyelitis
and immune-mediated demyelination to study the functional contributions of chemokine
and chemokine receptor expression in regulating neuroinflammation, host defense,
and disease development ii) evaluate the mechanisms by which chemokine and chemokine
receptors participate in linking innate and adaptive immune responses following
viral infection, iii) utilize a model of remyelination developed in my laboratory
to identify unique gene(s) involved in this complex process.
One major area of ongoing work in the laboratory is to study how chemokines
and chemokine receptors contribute to defense and disease following mouse hepatitis
virus (MHV) infection of the central nervous system (CNS). Persistent MHV infection
of the CNS results in an immune-mediated demyelinating disease that is similar
clinically and histologically to the human demyelinating disease Multiple Sclerosis
(MS). As such, the MHV system offers a relevant model to study the underlying
molecular and cellular mechanisms contributing to MS. Importantly, chemokines
and their receptors have been shown to be expressed within demyelinating lesions
present in MS patients and have been proposed to be important in contributing
to demyelination by attracting inflammatory cells into the CNS. Over the past
four years, we have systematically determined that expression of chemokine and
chemokine receptor genes is regulated within the CNS following MHV infection.
Specifically, studies have determined that expression of CXCL10/IP-10 (interferon
inducible protein 10 kDa) is important in host defense during acute disease
by attracting T lymphocytes into the CNS that participate in host defense. Conversely,
chronic expression of CXCL10/IP-10 is important in amplifying demyelination
by attracting T lymphocytes into the CNS of persistently infected mice. Other
chemokines such as CCL5/RANTES are also important in disease by attracting both
T lymphocytes and macrophages into the CNS of MHV-infected mice. In addition,
our laboratory has also determined that chemokine receptors including CCR2 and
CCR5 also enhance leukocyte accumulation within the CNS following MHV infection.
Collectively, these studies highlight the importance of chemokines and their
receptors in enhancing inflammation within the CNS of virally-infected mice
and indicate these molecules may be relevant targets for treatment of MS as
well as other neuroinflammatory diseases.
Additional efforts are now focused on understanding how chemokines/chemokine receptors regulate innate immunity within the CNS following viral infection as well as how chemokine signaling contributes to the generation of anti-viral effector T cells
Intracranial infection of mice with mouse hepatitis virus (MHV) results in a progressive demyelinating disease with clinical and histological similarities to the human disease multiple sclerosis. Mice that survive the acute phase of infection clear infectious virus below detectable levels by 12 days post infection. However, viral RNA and protein, as well as inflammatory T cells and macrophage persist within the CNS. The majority of these surviving mice develop a chronic demyelinating disease that is characterized clinically by abnormal gait and hind-limb paralysis, and histologically by wide spread myelin destruction within the CNS. Similar to MS both T cells and macrophages are important in contributing to demyelination in persistently infected mice. As inflammatory cells, including T cells and macrophages, are considered critical to disease pathogenesis, recent efforts have focused on characterizing the role of chemokines, small proteins that participate in leukocyte migration and trafficking in the pathogenesis of MS. Analysis of chemokine expression in mice chronically infected with MHV demonstrated that IP-10, a potent T cell chemoattractant, is expressed both within demyelinating lesions and surrounding parenchyma, which is consistent with expression of this molecule in MS lesions. The following movies illustrate the effect that neutralization of IP-10 has on demyelination in mice persistently infected with MHV. Mice were treated with either anti-IP-10, anti-Mig or control normal rabbit serum (NRS) beginning on day 12 p.i., which represents a time in which demyelination is established. Treatment with anti-IP-10 resulted in a significant reduction in clinical disease severity beginning at 15 days p.i. which lasted until day 21 p.i. During this time, mice treated with either anti-Mig or NRS exhibited hind-limb paralysis and limited mobility whereas anti-IP-10 treated mice displayed almost complete restoration of motor skills. Removal of anti-IP-10 treatment (day 20 p.i.) resulted in an increase in clinical disease severity such that by day 28 there were no differences between any experimental groups.
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Dr. Lane is part of the UCI Graduate Track in Virology within the UCI graduate Program in Molecular Biology, Genetics, and Biochemistry. Applications requests or additional information about the graduate program may be obtained by electronic mail at gp-mbgb@uci.edu or by phone at (949) 824-8145. On-line applications may also be submitted through the Office of Research and Graduate Studies.
1) Molecular Biology, Genetics, and Biochemistry
2) Email: gp-mbgb@uci.edu or call (949) 824-8145
To update this Web page, please contact Einstein@uci.edu
