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 Recent
advances in our understanding of how to present tumor
components to the immune system have fostered considerable
optimism for development of effective vaccines against
clones that produce lethal amyloid fibrils in primary
amyloidosis or against malignant cancer clones. Primary
amyloidosis is a lethal disorder involving expansion
of a plasma (lymphocyte) cell clone which produces protein
products (amyloid fibrils) which precipitate in and
compromise the function of several vital organs. Current
treatments for primary amyloidosis consist of a variety
of chemotherapeutics and are limited by significant
toxic side effects. In the Sherr laboratory, the "C"
team has taken advantage of the demonstration of extremely
high levels of AhR and AhR-regulated proteins (e.g.,
the cytochrome P450 CYP1B1) in human malignant plasma
cells by demonstrating that fragments of these proteins
can induce potent cytotoxic T cells which kill tumors
expressing high levels of the intact proteins.
Tahamtan Ahmadi, MD, has used peptides derived from tumor-associated
proteins, including the AhR and AhR-regulated CYP1B1,
that are predicted to induce cytolytic tumor-specific
T cell responses. Indeed, using a transgenic mouse model,
he has demonstrated that killer T cells can be generated
in vivo. Together with Nathalie Weizman, MA,
Ahmadi is maximizing production of these killer T cells
in vivo using techniques that are translatable
to the clinic. The ultimate goal of this project is to
apply what has been learned in animal models to the treatment
of B cell
malignancies
in general and primary (AL) amyloid in particular.
Amanda Flies,
a predoctoral fellow in the Boston Univseristy Immunology
Training Program, is extending this work to another,
plasma cell-specific target, i.e., the fibrillogenic
immunoglobulin light chain itself. Using bioinformatics,
Flies has identified light chain peptides predicted
to induce potent CD8 + killer T cell responses. She
is using these peptides to induce and to characterize
immune responses in transgenic mice. In addition, Flies
is characterizing amyloid plasma cells with regard to
surface phenotype and is attempting to grow populations
of human bone marrow T cells with the intention of expanding
naturally occurring amyloid plasma cell-specific CD4
+ and CD8 + T cells.
Yvonne Efeberra,
MD, is a hematology research fellow who is interested
in using activated B cells as efficient antigen-presenting
cells for amyloid and cancer immunotherapy. She has
been able to expand populations of CD40 ligand-activated
murine B cells from green fluorescent protein-transgenic
mice and has observed the migration pattern of these
potential antigen-presenting cells after injection into
wildtype hosts. In addition, Efeberra is using these
activated B cells as vehicles for carrying immunogenic
peptides, such as those studied by Ahmadi, Weizmann,
and Flies, to secondary lymphoid organs where the peptides
are predicted to induce tumor-specific responses.
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