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Related post: Hospital; Paul and Germain, LI, NIAID; Asofsky, LMI, NIAID; Sharrow and Sachs,
Immunology Branch, NCI).
Induction of self tolerance can explain certain forms of immune response gene
controlled responsiveness Viramune Xr .
The immune response to thymus dependent antigens depends upon the
activation of a series of immune response (Ijr) genes which encode class II
major histocompatibility complex molecules that are co-recognized with antigen
by histocompatibilty-restricted T cells. Strain 13 guinea pigs possess an Ir
gene which allows them to respond to antigenic determinants on the B chain of
bovine insulin. By contrast, strain 2 guinea pigs are unresponsive to these
antigenic determinants. Laboratory of Immunology scientists have attempted to
gain insight into the mechanisms responsible for this genetically controlled
difference in responsiveness to insulin B chain determinants. They have done
so by the induction of long term T cell lines from strain 13 guinea pigs
specific for insulin B chain determinants. Long term T cell lines prepared
from strain 13 T cells primed in vitro with insulin presented to them on
strain 13 antigen presenting cells express the specificity normally associated
with T cells from strain 13 animals immunized with insulin. That is, these T
cells respond to the insulin B chain antigenic determinants when presented by
strain 13 antigen presenting cells but not when presented by strain 2 antigen
presenting cells. However, it is possible to prime strain 13 T cells which
can respond to insulin when presented by strain 2 antigen presenting cells.
This process takes advantage of a technique described several years ago by
Drs. David Thomas and Ethan Shevach in the Laboratory of Immunology which
involves the initial elimination of alloreactive T cells through the use of
bromodeoxyuridine and light. The strain 13 T cell lines obtained, which
respond to insulin presented by strain 2 antigen presenting cells, have
several unique features. Firstly, they fail to react to insulin presented by
strain 13 antigen presenting cells indicating that they utilize strain 2
class II molecules as restriction elements. Secondly, they recognize the
insulin B chain in association with strain 2 antigen presenting cells. This
is of particular significance since strain 2 guinea pigs failed to Viramune 200 Mg make any
responses specific for insulin B chain determinants. Consequently, the
unresponsiveness of strain 2 guinea pigs cannot be due to a total incapacity
20-5
of strain 2 antigen presenting cells to present insulin B chain. Finally, the
strain 13 T cell lines which recognize insulin B chain on strain 2 antigen
presenting cells react equally well to bovine insulin and to guinea pig
insulin. This strongly suggests that strain 2 guinea pigs are unresponsive to
insulin B chain presented by strain 2 antigen presenting cells because the T
cell clones which might have reacted to it cross-react with self-insulin
presented by strain 2 antigen presenting cells and, thus, would have been
eliminated during the induction of self tolerance. This tolerance induction,
however, fails to eliminate T cell specific for insulin Cheap Viramune B chain associated
with strain 13 antigen presenting cells. These results thus indicate that the
process of tolerance induction to T cells is itself restricted by the major
histocompatibility complex; and secondly, that the T cell receptor repertoire
is shaped in the course of tolerance induction in such a way as to explain at
least certain instances of Ir gene controlled unresponsiveness. Finally,
these results indicate that in such cases, one cannot attribute
unresponsiveness dependent on Ir genes to a total incapacity of the antigen
presenting cell to process or present the antigen in question (Dos Reis and
Shevach, LI, NIAID).
Monoclonal antibody specific for receptors of MHC-restricted T cell clones .
One of the major problems facing cellular immunologists has been the
nature of the antigen binding receptor of T cells and, in particular, the
nature of the recognition structures involved in the phenomena of
histocompatibility restricted T cell interaction with antigen presenting cells
and B cells. The current availability of cloned long term T cell lines and T
cell hybridomas that are antigen specific has made possible more direct
approaches to the study of this problem than was formerly feasible.
Laboratory of Immunology scientists have now produced monoclonal antibodies
which appear to be specific for unique antigenic determinants associated with
the antigen specific receptors of such cloned T cell hybridomas. These
experiments involve the derivation of T cell hybridomas from BlOA T cells
specific for the carboxy terminal peptide of pigeon cytochrome c. Antibodies
were produced by immunizing (BALB/c x AKR)F, mice with one such T cell clone,
2B4. Monoclonal antibodies were derived which had the property that they
inhibited the response of 2B4 to pigeon cytochrome c as measured by the
failure of 284 to secrete interleukin 2 in the presence of cytochrome c
when the monoclonal antibody was present. A closely Viramune Online related hybridoma, 2C2,
also specific for the carboxy terminal fragment of pigeon cytochrome Buy Viramune c failed
to be inhibited in its activation by the monoclonal antibody, indicating a
high degree of specificity in the action of the antibody. This monoclonal
antibody bound to 2B4 but not 2C2 cells as demonstrated by flow
microfluorometry. The molecule on the surface of 2B4 which was recognized by
the monoclonal antibody was a heterodimer consisting of two disulfide linked
polypeptides, one of approximately 42,000 daltons, and the other, 48,000
daltons. The monoclonal antibody failed to precipitate such a molecule from
2C2 cells. Additional studies aimed at isolating and biochemically
characterizing this 85-90,000 dalton heterodimer are now underway. It seems
very likely that this molecule will prove to have the antigen binding
properties of the T cell receptor. In addition, efforts to molecularly clone
the genes which encode this molecule are also being undertaken (Samelson,
Germain, and Schwartz, LI, NIAID).
20-6
Receptor occupancy model for T cell activation
The availability of cloned long term lines of T cells makes possible a
detailed analysis of their requirements for activation. In particular, it is
possible to determine both the characteristics of the interaction of the
receptor with antigen on the surface of antigen presenting cells and what
fraction of receptors need to be occupied in order for an activation event to
occur. To begin this analysis, Laboratory of Immunology scientists have
examined the activation requirements of T cell clones propagated in vitro by
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