Determining the Quantitative Principles of T Cell Response to Antigenic Disparity in Stem Cell Transplantation

Abstract

Alloreactivity compromising clinical outcomes in stem cell transplantation is observed despite HLA matching of donors and recipients. This has its origin in the variation between the exomes of the two, which provides the basis for minor histocompatibility antigens (mHA). The mHA presented on the HLA class I and II molecules and the ensuing T cell response to these antigens results in graft vs. host disease. In this paper, results of a whole exome sequencing study are presented, with resulting alloreactive polymorphic peptides and their HLA class I and HLA class II (DRB1) binding affinity quantified. Large libraries of potentially alloreactive recipient peptides binding both sets of molecules were identified, with HLA-DRB1 generally presenting a greater number of peptides. These results are used to develop a quantitative framework to understand the immunobiology of transplantation. A tensor-based approach is used to derive the equations needed to determine the alloreactive donor T cell response from the mHA-HLA binding affinity and protein expression data. This approach may be used in future studies to simulate the magnitude of expected donor T cell response and determine the risk for alloreactive complications in HLA matched or mismatched hematopoietic cell and solid organ transplantation.

Clinical and basic implications of dynamic T cell receptor clonotyping in hematopoietic cell transplantation

“…The latter observation confirms the role of highly divergent HLA genotypes in eliciting diverse T cell specificities, also in the post-allo-HCT setting (29). Per extension, this aspect is in line with previous work showing how D/R HLA genotypes may shape the recipient minor histocompatibility immune peptidome responsible for the direction and the intensity of alloreactive responses (30).…”

Role of Radiation Based Conditioning Regimens in Patients With High-Risk AML Undergoing Allogenic Transplantation in Remission or Active Disease and Mechanisms of Post-Transplant Relapse

“…This down-regulation is observed with similar frequencies in both HLA compatible (MUD/MRD) and incompatible transplants (haplo and mMUD). In vitro studies have also shown that minor histocompatibility antigens presented by class II molecules far more efficiently compared to HLA class I molecules, implying that in the unrelated donor setting immune reactivity against minor antigens is more potent than against a few incompatible HLA molecules ( 72 ). The mechanism for down-regulation of HLA class II genes is not related to somatic mutation in HLA genes or other regulators.…”

A Model of Minor Histocompatibility Antigens in Allogeneic Hematopoietic Cell Transplantation

“…Although the diversity of peptides bound to class I and II HLA-molecules did not correlate with outcomes after HCT ( 9 ), the extent of genome-wide mismatching between siblings has been correlated with the risk of severe acute GVHD ( 10 ) and chronic GVHD ( 11 ). More sophisticated computational algorithms have been designed to predict the overall in vivo alloreactive T cell response ( 12 ), but their accuracy and utility have not yet been evaluated, and only limited progress has been made toward implicating individual mHAgs in outcomes after HCT in clinical studies ( 13 ).…”