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開催日時:平成20年 3月13日(木)16:00~1

講 師:Professor Diane Mathis
所 属:Joslin Diabetes Center&s_comma; The Harvard Stem Cell
Institute&s_comma; Harvard University

演 題:Novel determinants of the joint specificity of
autoimmune/inflammatory attack.

概  要:Antibodies against the ubiquitously expressed protein
glucose-6-phosphate-isomerase (GPI)induce arthritis in the K/BxN
mouse model. When serum containing these autoantibodies is injected
healthy mice&s_comma; the innate immune system is mobilized and arthritis
soon develops. This system has revealed novel mechanisms for
imposing tissue specificity on autoimmune/inflammatory processes. The
first has to do with restraints on activation of the alternative
pathway of complement: GPI is found constitutively aligned on the
acellular surface where the cartilage meets the articular cavity;
being acellular&s_comma; and thereby lacking cellular complement inhibitors&s_comma;
such a surface can permit complement activation that is effectively
extinguished at other sites. The second mechanism is related to the
vasculature: immune complexes&s_comma; even those entailing non-joint
antigens&s_comma; promote vascular leakage specifically at the joints&s_comma;
predisposing them to leukocytic infiltration. Thirdly&s_comma; there may also
be a role for regulatory T cells in containing inflammation to
particular tissues. Thus&s_comma; a tissue-specific disease need not issue
from reaction to a tissue-specific antigen&s_comma; but may instead reflect
structural/physiological particularities of the target site.

開催日時:平成20年 3月13日(木)17:00~18:00

講 師:Professor Cristophe Benoist
所 属:Joslin Diabetes Center&s_comma; The Harvard Stem Cell
Institute&s_comma; Harvard University

演 題:Commitment and differentiation to the FoxP3+
Treg lineage.

概  要:The CD4+CD25+ lineage of regulatory T (Treg) cells&s_comma;
characterized by the transcription factor Foxp3&s_comma; plays a key role in
controlling immune and autoimmune responses. Because of its
functional importance&s_comma; it is necessary to fully understand the
mechanisms that promote the differentiation of the Treg lineage.
Tregs originate primarily in the thymus&s_comma; where differentiation along
the Treg lineage follows cues imparted by the TCR&s_comma; leading to
distinct TCR repertoires in Treg and Tconv cells. Recent results
indicate that Akt/mTOR is an important element in inducing
differentiation along the Treg or Tconv pathways. Treg cells can also
be elicited by “conversion” of mature CD4+ T lymphocytes
to Foxp3-positivity by chronic antigenic stimulation&s_comma; homeostatic
expansion&s_comma; or activation in vitro with TGFb. Gene expression
profiling shows that these different modes of conversion do not
result in the same differentiated phenotype&s_comma; and that FoxP3 is not
the master regulator of the lineage&s_comma; as once thought. Retinoic Acid
(RA)&s_comma; the ubiquitous morphogen&s_comma; enhances TGFb-induced expression of
Foxp3. The action of RA is primarily indirect&s_comma; due to the inhibition
of “contra-conversion”&s_comma; an action of cells with a memory
phenotype&s_comma; which repress TGFb-induced conversion. We will discuss the
mechanisms of contra-conversion&s_comma; and its inhibition by retinoids via
the RARa.