Isoplexis_July2021_AcceleratingDevelopmentCurativeMedicines - 8

ACCELERATING THE DEVELOPMENT OF CURATIVE MEDICINES WITH FUNCTIONAL IMMUNE PROFILING
Identifying Key Drivers
of Transplant Rejection with
Single-Cell Immune Profiling
A
llograft rejection, the rejection of transplanted
tissue, is typically categorized
as cell-mediated or antibody-mediated.
The processes involved in cell-mediated and antibody-mediated
rejection can occur in combination,
causing mixed rejection of the allograft. In a recent
study, conducted by Xie, et al. IsoPlexis' single-cell
proteomics was used to characterize the relationship
between antibody-mediated deposition of
complement membrane attack complexes (MACs) on
IFN-γ-primed human endothelial cells (ECs) and T cell
proliferation, tying together the antibody-mediated
and cell-mediated processes involved in rejection.
IsoPlexis' walk-away functional immune landscaping
uncovered polyfunctional drivers of mixed allograft
rejection and identified agonists that suppressed the
detrimental effect of IFN-γ-primed ECs treated with
human alloantibodies called panel-reactive antibodies
(PRA).2
Human graft ECs express high levels of Class I
8 | GENengnews.com
and II MHC molecules, which are the main targets
of donor specific antibodies (DSAs) ECs are also
involved in cell-mediated rejection: they release
costimulatory signals that engage TEM
s, which
correlate with T cell-mediated rejection. DSAs
are directly identified by alloreactive T cells. ECs
can stimulate alloreactive CD8+ TEM
to rapidly
differentiate into cytotoxic lymphocytes (CTL) which
create effector molecules that can kill grafts, such
as perforin, granzymes, and cytokines. ECs can also
rapidly stimulate CD4+ TEM
that produce cytokines
that activate effector cells, such as more CTLs, B cells,
NK cells, and macrophages.
2 All of these effector cells
can contribute to allograft rejection. The magnitude
of T cell activation response depends on both the
strength of the antigen and the costimulatory signal
released by the EC: stronger signals produce more
potent and complex effector cells which release
complex combinations of effector molecules.2
provides a presumed mechanism through which
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Isoplexis_July2021_AcceleratingDevelopmentCurativeMedicines

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