41 research outputs found
In Silico Derivation of HLA-Specific Alloreactivity Potential from Whole Exome Sequencing of Stem Cell Transplant Donors and Recipients: Understanding the Quantitative Immuno-biology of Allogeneic Transplantation
Donor T cell mediated graft vs. host effects may result from the aggregate
alloreactivity to minor histocompatibility antigens (mHA) presented by the HLA
in each donor-recipient pair (DRP) undergoing stem cell transplantation (SCT).
Whole exome sequencing has demonstrated extensive nucleotide sequence variation
in HLA-matched DRP. Non-synonymous single nucleotide polymorphisms (nsSNPs) in
the GVH direction (polymorphisms present in recipient and absent in donor) were
identified in 4 HLA-matched related and 5 unrelated DRP. The nucleotide
sequence flanking each SNP was obtained utilizing the ANNOVAR software package.
All possible nonameric-peptides encoded by the non-synonymous SNP were then
interrogated in-silico for their likelihood to be presented by the HLA class I
molecules in individual DRP, using the Immune-Epitope Database (IEDB) SMM
algorithm. The IEDB-SMM algorithm predicted a median 18,396 peptides/DRP which
bound HLA with an IC50 of <500nM, and 2254 peptides/DRP with an IC50 of <50nM.
Unrelated donors generally had higher numbers of peptides presented by the HLA.
A similarly large library of presented peptides was identified when the data
was interrogated using the Net MHCPan algorithm. These peptides were uniformly
distributed in the various organ systems. The bioinformatic algorithm presented
here demonstrates that there may be a high level of minor histocompatibility
antigen variation in HLA-matched individuals, constituting an HLA-specific
alloreactivity potential. These data provide a possible explanation for how
relatively minor adjustments in GVHD prophylaxis yield relatively similar
outcomes in HLA matched and mismatched SCT recipients.Comment: Abstract: 235, Words: 6422, Figures: 7, Tables: 3, Supplementary
figures: 2, Supplementary tables:
Stem Cell Transplantation As A Dynamical System: Are Clinical Outcomes Deterministic?
Outcomes in stem cell transplantation (SCT) are modeled using probability
theory. However the clinical course following SCT appears to demonstrate many
characteristics of dynamical systems, especially when outcomes are considered
in the context of immune reconstitution. Dynamical systems tend to evolve over
time according to mathematically determined rules. Characteristically, the
future states of the system are predicated on the states preceding them, and
there is sensitivity to initial conditions. In SCT, the interaction between
donor T cells and the recipient may be considered as such a system in which,
graft source, conditioning and early immunosuppression profoundly influence
immune reconstitution over time. This eventually determines clinical outcomes,
either the emergence of tolerance or the development of graft versus host
disease. In this paper parallels between SCT and dynamical systems are explored
and a conceptual framework for developing mathematical models to understand
disparate transplant outcomes is proposed.Comment: 23 pages, 4 figures. Updated version with additional data, 2 new
figures and editorial revisions. New authors adde
Cytomegalovirus Antigenic Mimicry of Human Alloreactive Peptides: A Potential Trigger for Graft versus Host Disease
The association between human cytomegalovirus (hCMV) reactivation and the
development of graft-versus-host-disease (GVHD) has been observed in stem cell
transplantation (SCT). Seventy seven SCT donor-recipient pairs (DRP) (HLA
matched unrelated donor (MUD), n=50; matched related donor (MRD), n=27)
underwent whole exome sequencing to identify single nucleotide polymorphisms
(SNPs) generating alloreactive peptide libraries for each DRP (9-mer
peptide-HLA complexes); Human CMV CROSS (Cross-Reactive Open Source Sequence)
Database was compiled from NCBI; HLA class I binding affinity for each DRPs HLA
was calculated by NetMHCpan 2.8 and hCMV- derived 9-mers algorithmically
compared to the alloreactive peptide-HLA complex libraries. Short consecutive
(6 or greater) amino acid (AA) sequence homology matching hCMV to recipient
peptides was considered for HLA-bound-peptide (IC50<500 nM) cross reactivity.
Of the 70,686 hCMV 9-mers contained within the hCMV CROSS database, 29,658.8
+/- 9038.5 were found to match MRD DRP alloreactive peptides and 52,910.2 +/-
16121.8 matched MUD DRP peptides (Student's T-test, p<0.001). In silico
analysis revealed multiple high affinity, immunogenic CMV-Human peptide matches
(IC50<500 nM) expressed in GVHD-affected tissue-specific manner (proteins
expressed at 10 RPKM or greater). hCMV+GVHD was found in 18 patients, 13
developing hCMV viremia before GVHD onset with a subset analysis of 7 instances
of hCMV viremia prior to acute GVHD onset (n=3), chronic GVHD (n=2) and acute +
chronic GVHD (n=2) indicating cross reactive peptide expression within affected
organs. We propose that based on our analysis and preliminary clinical
correlations that hCMV immune cross-reactivity may cause antigenic mimicry of
human alloreactive peptides triggering GVHD.Comment: Pre-submission manuscript, 4 tables, 5 figures, 2 supplements & 2
Appendices-available upon request from first autho
Whole Exome Sequencing to Estimate Alloreactivity Potential Between Donors and Recipients in Stem Cell Transplantation
Whole exome sequencing was performed on HLA-matched stem cell donors and
transplant recipients to measure sequence variation contributing to minor
histocompatibility antigen differences between the two. A large number of
nonsynonymous single nucleotide polymorphisms were identified in each of the
nine unique donor-recipient pairs tested. This variation was greater in
magnitude in unrelated donors as compared with matched related donors.
Knowledge of the magnitude of exome variation between stem cell transplant
recipients and donors may allow more accurate titration of immunosuppressive
therapy following stem cell transplantation.Comment: 12 pages- main article, 29 pages total, 5 figures, 1 supplementary
figur
Dynamical System Modeling of Immune Reconstitution after Allogeneic Stem Cell Transplantation Identifies Patients at Risk for Adverse Outcomes
AbstractSystems that evolve over time and follow mathematical laws as they evolve are called dynamical systems. Lymphocyte recovery and clinical outcomes in 41 allograft recipients conditioned using antithymocyte globulin (ATG) and 4.5-Gy total body irradiation were studied to determine if immune reconstitution could be described as a dynamical system. Survival, relapse, and graft-versus-host disease (GVHD) were not significantly different in 2 cohorts of patients receiving different doses of ATG. However, donor-derived CD3+ cell reconstitution was superior in the lower ATG dose cohort, and there were fewer instances of donor lymphocyte infusion (DLI). Lymphoid recovery was plotted in each individual over time and demonstrated 1 of 3 sigmoid growth patterns: Pattern A (n = 15) had rapid growth with high lymphocyte counts, pattern B (n = 14) had slower growth with intermediate recovery, and pattern C (n = 10) had poor lymphocyte reconstitution. There was a significant association between lymphocyte recovery patterns and both the rate of change of donor-derived CD3+ at day 30 after stem cell transplantation (SCT) and clinical outcomes. GVHD was observed more frequently with pattern A, relapse and DLI more so with pattern C, with a consequent survival advantage in patients with patterns A and B. We conclude that evaluating immune reconstitution after SCT as a dynamical system may differentiate patients at risk of adverse outcomes and allow early intervention to modulate that risk
Sequence homology between HLA-bound cytomegalovirus and human peptides: A potential trigger for alloreactivity.
Human cytomegalovirus (hCMV) reactivation may often coincide with the development of graft-versus-host-disease (GVHD) in stem cell transplantation (SCT). Seventy seven SCT donor-recipient pairs (DRP) (HLA matched unrelated donor (MUD), n = 50; matched related donor (MRD), n = 27) underwent whole exome sequencing to identify single nucleotide polymorphisms (SNPs) generating alloreactive peptide libraries for each DRP (9-mer peptide-HLA complexes); Human CMV CROSS (Cross-Reactive Open Source Sequence) database was compiled from NCBI; HLA class I binding affinity for each DRPs HLA was calculated by NetMHCpan 2.8 and hCMV- derived 9-mers algorithmically compared to the alloreactive peptide-HLA complex libraries. Short consecutive (≥6) amino acid (AA) sequence homology matching hCMV to recipient peptides was considered for HLA-bound-peptide (IC5