6 research outputs found
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
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