So thank you Dr. Schwartz for
that comprehensive and detailed overview of the pathogenesis of lupus and
our current understanding of the contributions both of
the innate immune system and
the adaptive immune system in the pathogenesis of this complex disease.
Now, it's time to move to therapies.
"Therapies: now and in the future."
So in our therapies now,
I don't want to focus on traditional immunosuppressive medications,
those given by mouth which while effective,
do have a plethora of side-effects,
many of which can be quite severe.
We do hope that targeting our therapies to
key mediators of the pathogenesis reviewed by Dr. Schwartz,
will be at least as effective as
those non-specific immunosuppressive medications that we're using today.
If not more effective,
while at the same time having less off target toxicity.
So we want to review the therapeutic strategy and I divided
it that discussion into B-cell targeting agents,
those that target T-cells and co-stimulation,
those agents that target innate immunity.
Perhaps, those that can induce tolerance,
agents that are directed against the complement system and
maybe the most promising recent development in the therapy of lupus,
those small molecules signaling inhibitors.
So first, we want to focus our discussion on B-cell targeting agents.
Of course, considering the important role of B-cells in the pathogenesis of lupus and
specifically of autoantibodies in induction of target organ damage in this disease,
in the skin, in the kidney, in the brain,
and other organs, this is a particular target of interest.
One which of course is already in clinical use is by
inhibiting the BAFF or BLyS/APRIL axis.
So we know that activated neutrophils and dendritic cells
secrete the cytokine called BLyS or BAFF as well as APRIL.
These are important cytokines that are important in driving B-cell activation, survival,
and generating those antibody-producing B- cells,
and their action is mediated through a number of cognitive receptors on lymphocytes.
There are three main receptors for BLyS and APRIL.
One is, the BAFF receptor or BAFF-R. The second is,
BCMA, and the third is TACI.
As you see in the image,
there's some cross talk between BLyS and APRIL signaling.