Quantitative relationship between the magnitude of variation in minor histocompatibility antigens (mHA) and graft versus host disease (GVHD) pathophysiology in stem cell transplant (SCT) donor-recipient pairs (DRP) is not established. In order to elucidate this relationship, whole exome sequencing (WES) was performed on 27 HLA matched related (MRD), & 50 unrelated donors (URD), to identify nonsynonymous single nucleotide polymorphisms (SNPs). An average 2,463 SNPs were identified in MRD, and 4,287 in URD DRP (p<0.01); resulting peptide antigens that may be presented on HLA class I molecules in each DRP were derived in silico (NetMHCpan ver2.0) and the tissue expression of proteins these were derived from determined (GTex). MRD DRP had an average 3,670 HLA-binding-alloreactive peptides, putative mHA (pmHA) with an IC50 of <500 nM, and URD, had 5,386 (p<0.01). To simulate an alloreactive donor cytotoxic T cell response, the array of pmHA in each patient was considered as an operator matrix modifying a hypothetical cytotoxic T cell clonal vector matrix; each responding T cell clone’s proliferation was determined by the logistic equation of growth, accounting for HLA binding affinity and tissue expression of each alloreactive peptide. The resulting simulated organ-specific alloreactive T cell clonal growth revealed marked variability, with the T cell count differences spanning orders of magnitude between different DRP. Despite an estimated, uniform set of constants used in the model for all DRP, and a heterogeneously treated group of patients, higher total and organ-specific T cell counts were associated with cumulative incidence of moderate to severe GVHD in recipients. In conclusion, exome wide sequence differences and the variable alloreactive peptide binding to HLA in each DRP yields a large range of possible alloreactive donor T cell responses. Our findings also help understand the apparent randomness observed in the development of alloimmune responses.
Immune reconstitution kinetics and subsequent clinical outcomes in HLA-matched recipients of allogeneic stem cell transplantation (SCT) are variable and difficult to predict. Considering SCT as a dynamical system, may allow sequence differences across the exomes of the transplant donors and recipients to be used to simulate an alloreactive T cell response, which may allow better clinical outcome prediction. To accomplish this, whole exome sequencing was performed on 34 HLA matched SCT donor-recipient pairs (DRP), and the nucleotide sequence differences translated to peptides. The binding affinity of the peptides to the relevant HLA in each DRP was determined. The resulting array of peptide-HLA binding affinity values in each patient was considered as an operator modifying a hypothetical T cell repertoire vector, in which each T cell clone proliferates in accordance to the logistic equation of growth. Using an iterating system of matrices, each simulated T cell clone's growth was calculated with the steady state population being proportional to the magnitude of the binding affinity of the driving HLA-peptide complex. Incorporating competition between T cell clones responding to different HLA-peptide complexes reproduces a number of features of clinically observed T cell clonal repertoire in the simulated repertoire. These include, sigmoidal growth kinetics of individual T cell clones and overall repertoire, Power Law clonal frequency distribution, increase in repertoire complexity over time with increasing clonal diversity and finally, alteration of clonal dominance when a different antigen array is encountered, such as in stem cell transplantation. The simulated, alloreactive T cell repertoire was markedly different in HLA matched DRP. The patterns were differentiated by rate of growth, and steady state magnitude of the simulated T cell repertoire and demonstrate a possible correlation with survival. In conclusion, exome wide sequence differences in DRP may allow simulation of donor alloreactive T cell response to recipient antigens and may provide a quantitative basis for refining donor selection and titration of immunosuppression following SCT.
The development of alloreactivity following stem cell transplantation (SCT) in HLA matched donorrecipient pairs (DRP) appears to be random. Minor histocompatibility antigens (mHA) are critical in graft versus host disease (GVHD) pathophysiology however, the quantitative relationship between GVHD and the magnitude of mHA in donor-recipient pairs (DRP) is not known. Whole exome sequencing (WES) was performed on 27 HLA matched related donors (MRD), & 50 unrelated (URD), to identify nonsynonymous single nucleotide polymorphisms (SNPs) with an average 2,490 SNPs were identified in MRD,and 4,287 in URD DRP (p<0.01). The resulting peptide antigens that may be presented on the relevant HLA class I molecules in each DRP were derived in silico (NetMHCpan ver2.0) and the tissue expression of proteins these were derived from determined (GTex). MRD DRP had an average 3,626 HLA-alloreactive peptide (AP) complexes with an IC50 of <500 nM and URD, had 5,386 (p<0.01). To simulate a donor cytotoxic T cell response to these AP, the array of HLA-AP complexes in each patient was considered as an operator matrix modifying a hypothetical cytotoxic T cell clonal vector matrix in which each responding T cell clone's proliferation is quantified by the logistic equation of growth. The simulated steady state T cell clonal response to the AP-HLA complexes in each DRP, accounted for the HLA binding affinity and expression of each AP. The resulting simulated organ-specific alloreactive T cell clonal growth revealed marked variability between different DRP. The sum of all T cell clones for common GVHD target organs was: MRD, median 188,821 cytotoxic T cells at steady state (n=26), MUD, 201,176 (n=35), single locus HLA-mismatch MUD: 56,229 (n=10). Despite an estimated, uniform set of constants used in the model for all DRP, and a heterogeneously treated group of patients, overall there was a non-significant trend for higher organ specific T cell counts in patients with GVHD compared to those with none, with weak associations observed for GVHD of the liver. In conclusion, exome wide sequence differences and the variable AP binding affinity to the HLA in each DRP yields a large range of possible alloreactive donor T cell responses possibly explaining the random nature of alloimmune responses observed in clinical practice. Incorporating other quantitative sources of T cell response variability may allow simulations like this to accurately model alloreactivity in SCT in the future.
Immune reconstitution kinetics and subsequent clinical outcomes in HLA-matched recipients of allogeneic stem cell transplantation (SCT) are variable and difficult to predict. Considering SCT as a dynamical system, may allow sequence differences across the exomes of the transplant donors and recipients to be used to simulate an alloreactive T cell response, which may allow better clinical outcome prediction. To accomplish this, whole exome sequencing was performed on 34 HLA matched SCT donor-recipient pairs (DRP), and the nucleotide sequence differences translated to peptides. The binding affinity of the peptides to the relevant HLA in each DRP was determined. The resulting array of peptide-HLA binding affinity values in each patient was considered as an operator modifying a hypothetical T cell repertoire vector, in which each T cell clone proliferates in accordance to the logistic equation of growth. Using an iterating system of matrices, each simulated T cell clone's growth was calculated with the steady state population being proportional to the magnitude of the binding affinity of the driving HLA-peptide complex. Incorporating competition between T cell clones responding to different HLA-peptide complexes reproduces a number of features of clinically observed T cell clonal repertoire in the simulated repertoire. These include, sigmoidal growth kinetics of individual T cell clones and overall repertoire, Power Law clonal frequency distribution, increase in repertoire complexity over time with increasing clonal diversity and finally, alteration of clonal dominance when a different antigen array is encountered, such as in stem cell transplantation. The simulated, alloreactive T cell repertoire was markedly different in HLA matched DRP. The patterns were differentiated by rate of growth, and steady state magnitude of the simulated T cell repertoire and demonstrate a possible correlation with survival. In conclusion, exome wide sequence differences in DRP may
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