TY - JOUR
T1 - Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases
AU - Beeton, Christine
AU - Wulff, Heike
AU - Standifer, Nathan E.
AU - Azam, Philippe
AU - Mullen, Katherine M.
AU - Pennington, Michael W.
AU - Kolski-Andreaco, Aaron
AU - Wei, Eric
AU - Grino, Alexandra
AU - Counts, Debra R.
AU - Wang, Ping H.
AU - LeeHealey, Christine J.
AU - Andrews, Brian S.
AU - Sankaranarayanan, Ananthakrishnan
AU - Homerick, Daniel
AU - Roeck, Werner W.
AU - Tehranzadeh, Jamshid
AU - Stanhope, Kimber L.
AU - Zimin, Pavel
AU - Havel, Peter J.
AU - Griffey, Stephen
AU - Knaus, Hans Guenther
AU - Nepom, Gerald T.
AU - Gutman, George A.
AU - Calabresi, Peter A.
AU - Chandy, K. George
PY - 2006/11/14
Y1 - 2006/11/14
N2 - Autoreactive memory T lymphocytes are implicated in the pathogenesis of autoimmune diseases. Here we demonstrate that disease-associated autoreactive T cells from patients with type-1 diabetes mellitus or rheumatoid arthritis (RA) are mainly CD4+CCR7-CD45RA- effector memory T cells (TEM cells) with elevated Kv1.3 potassium channel expression. In contrast, T cells with other antigen specificities from these patients, or autoreactive T cells from healthy individuals and disease controls, express low levels of Kv1.3 and are predominantly naïve or central-memory (T CM) cells. In TEM cells, Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kvβ2, SAP97, ZIP, p56lck, and CD4. Although Kv1.3 inhibitors [ShK(L5)-amide (SL5) and PAP1] do not prevent immunological synapse formation, they suppress Ca2+-signaling, cytokine production, and proliferation of autoantigen-specific TEM cells at pharmacologically relevant concentrations while sparing other classes of T cells. Kv1.3 inhibitors ameliorate pristane-induced arthritis in rats and reduce the incidence of experimental autoimmune diabetes in diabetes-prone (DP-BB/W) rats. Repeated dosing with Kv1.3 inhibitors in rats has not revealed systemic toxicity. Further development of Kv1.3 blockers for autoimmune disease therapy is warranted.
AB - Autoreactive memory T lymphocytes are implicated in the pathogenesis of autoimmune diseases. Here we demonstrate that disease-associated autoreactive T cells from patients with type-1 diabetes mellitus or rheumatoid arthritis (RA) are mainly CD4+CCR7-CD45RA- effector memory T cells (TEM cells) with elevated Kv1.3 potassium channel expression. In contrast, T cells with other antigen specificities from these patients, or autoreactive T cells from healthy individuals and disease controls, express low levels of Kv1.3 and are predominantly naïve or central-memory (T CM) cells. In TEM cells, Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kvβ2, SAP97, ZIP, p56lck, and CD4. Although Kv1.3 inhibitors [ShK(L5)-amide (SL5) and PAP1] do not prevent immunological synapse formation, they suppress Ca2+-signaling, cytokine production, and proliferation of autoantigen-specific TEM cells at pharmacologically relevant concentrations while sparing other classes of T cells. Kv1.3 inhibitors ameliorate pristane-induced arthritis in rats and reduce the incidence of experimental autoimmune diabetes in diabetes-prone (DP-BB/W) rats. Repeated dosing with Kv1.3 inhibitors in rats has not revealed systemic toxicity. Further development of Kv1.3 blockers for autoimmune disease therapy is warranted.
KW - Effector memory T cell
KW - Rheumatoid arthritis
KW - Type-1 diabetes mellitus
UR - http://www.scopus.com/inward/record.url?scp=33751232672&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33751232672&partnerID=8YFLogxK
U2 - 10.1073/pnas.0605136103
DO - 10.1073/pnas.0605136103
M3 - Article
C2 - 17088564
AN - SCOPUS:33751232672
SN - 0027-8424
VL - 103
SP - 17414
EP - 17419
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 46
ER -