High-resolution tracking of T cell differentiation to predict and control alloreactive disease

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative therapy for many
malignant and non-malignant diseases. Despite advances in allo-HSCT, graft-versus-host disease (GVHD)
remains a significant cause of morbidity and mortality in patients. GVHD is marked by the activation of donor
alloreactive T cells which target and damage healthy recipient tissues. This project’s central hypothesis is that
donor alloreactive T cells differentiate into immunoregulatory or pro-inflammatory effectors depending on the
environment into which they are transplanted and that identifying these alloreactive cells by high-resolution
sequencing can predict clinical GVHD. My long-term career goal is to use high-resolution bioinformatics to
dissect the distinct differentiation pathways which lead to tolerance versus alloreactivity after adoptive cell
therapy. Consequently, this proposal has three main aims. During the mentored K99 phase of this award, we
first hypothesize that alloreactive T cell subsets develop their phenotype after allo-HSCT and that the detection
of anti-human T cells can predict GVHD after allo-HSCT. Second, during the independent R00 phase, we posit
that these and other T cell subsets arise from naïve T cells in response to allo-antigen and we will investigate
the mechanisms which drive this differentiation in both human and mouse. Third, we propose that specific T cells
which mediate alloreactive GVHD responses will be identifiable after allo-HSCT and experiments in Aim 3 will
utilize high-resolution sequencing techniques to identify and track alloreactive T cells in both xenogeneic and
murine models of GVHD. These scientific aims will be explored alongside additional training in human
experimental methods, advanced bioinformatics and machine learning, career development, and clinical
translation with the support of a highly experienced, multidisciplinary mentoring team. The overall objective of
this proposal will be to develop the ability to track alloreactive T cells in patients to predict disease onset prior to
the emergence of deleterious symptoms. These novel results will be directly applicable to the field of allo-HSCT
as well as other contexts involving alloreactive T cell responses including solid organ transplantation, chimeric
antigen receptor T cell therapy, and other adoptive T cell therapies.

Grant Number: 1K99HL179392-01
NIH Institute/Center: NIH
Principal Investigator: Cameron Bader