Core A: Elucidating the Mechanisms Underlying Mixed-Chimerism Based Tolerance

CORE SUMMARY / ABSTRACT
Tolerance of kidney allografts has been achieved in monkeys and patients via transient mixed hematopoietic
chimerism. However, until now, our current mixed chimerism protocols have consistently failed to induce
tolerance of other more immunogenic transplants, including hearts. Enhancing our mixed chimerism strategy to
achieve tolerance of heart allografts is the main objective of our overall Program. We will accomplish this
objective by testing the overall hypothesis that enhancing current mixed chimerism protocols using novel
strategies that achieve durable, high level donor chimerism will lead to an effective and safe tolerance protocol
that can be rapidly translated to human recipients of heart allografts. The specific goal of Core A is to test
mechanistic hypotheses generated by the in vivo treatments described in Projects 1-3. Improving our
mechanistic understanding of tolerance inducing procedures that work and those that do not will inform the
design of future protocols. We will test these mechanistic hypotheses by 1) deciphering the mechanisms by
which donor hematopoietic mixed chimerism, leukocyte recovery, and alloimmunity by memory T cells affect
tolerance induction, 2) determining if successful tolerance protocols are associated with extracellular vesicle
generation and donor antigen cross-dressing, and 3) evaluating the role of T cell deletion and regulation in
rejection vs. tolerance. Understanding the mechanisms driving the immune response towards rejection or
tolerance in monkeys treated with the mixed chimerism protocols described in Projects 1-3 will contribute greatly
to the refinement of those protocols and to the design of future tolerance strategies that can be tested in Projects
1-3 in anticipation of rapid translation to human heart transplant recipients.

Grant Number: 5P01HL158504-05
NIH Institute/Center: NIH
Principal Investigator: GILLES BENICHOU