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In silico Derivation of HLA-Specific Alloreactivity Potential from Whole Exome Sequencing of Stem-Cell Transplant Donors and Recipients: Understanding the Quantitative Immunobiology of Allogeneic Transplantation.

Jameson-Lee M, Koparde V, Griffith P, Scalora AF, Sampson JK, Khalid H, Sheth NU, Batalo M, Serrano MG, Roberts CH, Hess ML, Buck GA, Neale MC, Manjili MH, Toor AA - Front Immunol (2014)

Bottom Line: All the possible nonameric peptides incorporating the variant amino acid resulting from these SNPs were interrogated in silico for their likelihood to be presented by the HLA class I molecules using the Immune Epitope Database stabilized matrix method (SMM) and NetMHCpan algorithms.A similar library of presented peptides was identified when the data were interrogated using the NetMHCpan algorithm.The bioinformatic algorithm presented here demonstrates that there may be a high level of mHA variation in HLA-matched individuals, constituting a HLA-specific alloreactivity potential.

View Article: PubMed Central - PubMed

Affiliation: Stem Cell Transplant Program, Massey Cancer Center, Virginia Commonwealth University , Richmond, VA , USA.

ABSTRACT
Donor T-cell mediated graft versus host (GVH) effects may result from the aggregate alloreactivity to minor histocompatibility antigens (mHA) presented by the human leukocyte antigen (HLA) molecules in each donor-recipient pair undergoing stem-cell transplantation (SCT). Whole exome sequencing has previously demonstrated a large number of non-synonymous single nucleotide polymorphisms (SNP) present in HLA-matched recipients of SCT donors (GVH direction). The nucleotide sequence flanking each of these SNPs was obtained and the amino acid sequence determined. All the possible nonameric peptides incorporating the variant amino acid resulting from these SNPs were interrogated in silico for their likelihood to be presented by the HLA class I molecules using the Immune Epitope Database stabilized matrix method (SMM) and NetMHCpan algorithms. The SMM algorithm predicted that a median of 18,396 peptides weakly bound HLA class I molecules in individual SCT recipients, and 2,254 peptides displayed strong binding. A similar library of presented peptides was identified when the data were interrogated using the NetMHCpan algorithm. The bioinformatic algorithm presented here demonstrates that there may be a high level of mHA variation in HLA-matched individuals, constituting a HLA-specific alloreactivity potential.

No MeSH data available.


Related in: MedlinePlus

A quantitative model for the development of GVHD. Whole exome sequencing identifies all the nsSNP with a GVH vector, yielding a putative alloreactivity potential, which may be a function (f) of the cumulative influence of these polymorphisms. This is represented as a series, listing the sequence of polymorphic exome loci. Substituting individual nsSNPGVH in the equation by peptide-HLA binding affinity (reciprocal of IC50)*relative expression level of the gene bearing the nsSNPGVH (for each HLA molecule) yields the HLA-specific alloreactivity potential, in this Re is the relative expression of protein with nsSNPGVH and resulting peptides. In this series, the expression, Rep1*(1/IC50P1-HLA-A1) for each specific peptide-HLA complex, hypothetically represents the T-cell clone-specific AP. Multiple peptides constituting this series then drive a proportional oligoclonal T-cell expansion in GVHD, as many different mHA are presented by the HLA in an individual, the final distribution conforming to the Power law. Since T-cell clonal expansion in response to presented antigens may be influenced by factors such as tissue injury, cytokine milieu, and immunosuppression intensity; the GVHD likelihood, and its phenotype may in turn be determined not only by the ubiquitous mHA but also by the tissue volume and its state (inflammation/injury), and most importantly time at which organ injury/inflammation occurs relative to T-cell infusion.
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Figure 7: A quantitative model for the development of GVHD. Whole exome sequencing identifies all the nsSNP with a GVH vector, yielding a putative alloreactivity potential, which may be a function (f) of the cumulative influence of these polymorphisms. This is represented as a series, listing the sequence of polymorphic exome loci. Substituting individual nsSNPGVH in the equation by peptide-HLA binding affinity (reciprocal of IC50)*relative expression level of the gene bearing the nsSNPGVH (for each HLA molecule) yields the HLA-specific alloreactivity potential, in this Re is the relative expression of protein with nsSNPGVH and resulting peptides. In this series, the expression, Rep1*(1/IC50P1-HLA-A1) for each specific peptide-HLA complex, hypothetically represents the T-cell clone-specific AP. Multiple peptides constituting this series then drive a proportional oligoclonal T-cell expansion in GVHD, as many different mHA are presented by the HLA in an individual, the final distribution conforming to the Power law. Since T-cell clonal expansion in response to presented antigens may be influenced by factors such as tissue injury, cytokine milieu, and immunosuppression intensity; the GVHD likelihood, and its phenotype may in turn be determined not only by the ubiquitous mHA but also by the tissue volume and its state (inflammation/injury), and most importantly time at which organ injury/inflammation occurs relative to T-cell infusion.

Mentions: Can these findings be used to develop a clinically relevant model for allogeneic SCT? One possible explanation of the variant outcomes following SCT is that post-transplant emergent T-cell clones either develop tolerance to the many antigens encountered or fail to do so depending on the milieu encountered in the host. Early interventions, such as administration of anti-thymocyte globulin, (33) bortezomib, or post-transplant cyclophosphamide have a large impact on late post-transplant outcomes. Similar tolerance induction is observed following cellular interventions such as regulatory T-cell infusion and conditioning, which up regulates NK-T-cells at the time of SCT (34). This suggest that if a large antigenic pressure from the HLA-specific alloreactivity potential exists in all patients, then tissue injury and cytokine milieu at the time of SCT may be influential in determining the development of GVHD. Thus, if there is tissue injury following SCT, even if it is sub-clinical, multiple antigens are presented, then in the absence of adequate immunosuppression, the T-cell repertoire that develops results in the development of GVHD. On the other hand, if tissue injury is minimized and there is adequate immunosuppression, when the initial T-cell antigen-presenting cell interactions take place, peripheral (or central) tolerance would emerge. Following that, depending on the presence or absence of thymic tissue, T-cell clones developing from infused stem cells may perpetuate this process based on the prevailing T-cell population and target-tissue antigen presentation, perhaps influenced by the state of tissue injury (Figure 7). In such a model, inflammation provoked by the acute GVHD initiated by infused donor-derived T-cells reacting to recipient antigens is perpetuated in the form of “auto-reactivity” by the T-cells, developing from infused stem cells in the absence of normal thymic processing. This concept may not be novel in itself; however, our model provides a biologically plausible explanation reconciling mHA differences observed in HLA-matched DRP.


In silico Derivation of HLA-Specific Alloreactivity Potential from Whole Exome Sequencing of Stem-Cell Transplant Donors and Recipients: Understanding the Quantitative Immunobiology of Allogeneic Transplantation.

Jameson-Lee M, Koparde V, Griffith P, Scalora AF, Sampson JK, Khalid H, Sheth NU, Batalo M, Serrano MG, Roberts CH, Hess ML, Buck GA, Neale MC, Manjili MH, Toor AA - Front Immunol (2014)

A quantitative model for the development of GVHD. Whole exome sequencing identifies all the nsSNP with a GVH vector, yielding a putative alloreactivity potential, which may be a function (f) of the cumulative influence of these polymorphisms. This is represented as a series, listing the sequence of polymorphic exome loci. Substituting individual nsSNPGVH in the equation by peptide-HLA binding affinity (reciprocal of IC50)*relative expression level of the gene bearing the nsSNPGVH (for each HLA molecule) yields the HLA-specific alloreactivity potential, in this Re is the relative expression of protein with nsSNPGVH and resulting peptides. In this series, the expression, Rep1*(1/IC50P1-HLA-A1) for each specific peptide-HLA complex, hypothetically represents the T-cell clone-specific AP. Multiple peptides constituting this series then drive a proportional oligoclonal T-cell expansion in GVHD, as many different mHA are presented by the HLA in an individual, the final distribution conforming to the Power law. Since T-cell clonal expansion in response to presented antigens may be influenced by factors such as tissue injury, cytokine milieu, and immunosuppression intensity; the GVHD likelihood, and its phenotype may in turn be determined not only by the ubiquitous mHA but also by the tissue volume and its state (inflammation/injury), and most importantly time at which organ injury/inflammation occurs relative to T-cell infusion.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222229&req=5

Figure 7: A quantitative model for the development of GVHD. Whole exome sequencing identifies all the nsSNP with a GVH vector, yielding a putative alloreactivity potential, which may be a function (f) of the cumulative influence of these polymorphisms. This is represented as a series, listing the sequence of polymorphic exome loci. Substituting individual nsSNPGVH in the equation by peptide-HLA binding affinity (reciprocal of IC50)*relative expression level of the gene bearing the nsSNPGVH (for each HLA molecule) yields the HLA-specific alloreactivity potential, in this Re is the relative expression of protein with nsSNPGVH and resulting peptides. In this series, the expression, Rep1*(1/IC50P1-HLA-A1) for each specific peptide-HLA complex, hypothetically represents the T-cell clone-specific AP. Multiple peptides constituting this series then drive a proportional oligoclonal T-cell expansion in GVHD, as many different mHA are presented by the HLA in an individual, the final distribution conforming to the Power law. Since T-cell clonal expansion in response to presented antigens may be influenced by factors such as tissue injury, cytokine milieu, and immunosuppression intensity; the GVHD likelihood, and its phenotype may in turn be determined not only by the ubiquitous mHA but also by the tissue volume and its state (inflammation/injury), and most importantly time at which organ injury/inflammation occurs relative to T-cell infusion.
Mentions: Can these findings be used to develop a clinically relevant model for allogeneic SCT? One possible explanation of the variant outcomes following SCT is that post-transplant emergent T-cell clones either develop tolerance to the many antigens encountered or fail to do so depending on the milieu encountered in the host. Early interventions, such as administration of anti-thymocyte globulin, (33) bortezomib, or post-transplant cyclophosphamide have a large impact on late post-transplant outcomes. Similar tolerance induction is observed following cellular interventions such as regulatory T-cell infusion and conditioning, which up regulates NK-T-cells at the time of SCT (34). This suggest that if a large antigenic pressure from the HLA-specific alloreactivity potential exists in all patients, then tissue injury and cytokine milieu at the time of SCT may be influential in determining the development of GVHD. Thus, if there is tissue injury following SCT, even if it is sub-clinical, multiple antigens are presented, then in the absence of adequate immunosuppression, the T-cell repertoire that develops results in the development of GVHD. On the other hand, if tissue injury is minimized and there is adequate immunosuppression, when the initial T-cell antigen-presenting cell interactions take place, peripheral (or central) tolerance would emerge. Following that, depending on the presence or absence of thymic tissue, T-cell clones developing from infused stem cells may perpetuate this process based on the prevailing T-cell population and target-tissue antigen presentation, perhaps influenced by the state of tissue injury (Figure 7). In such a model, inflammation provoked by the acute GVHD initiated by infused donor-derived T-cells reacting to recipient antigens is perpetuated in the form of “auto-reactivity” by the T-cells, developing from infused stem cells in the absence of normal thymic processing. This concept may not be novel in itself; however, our model provides a biologically plausible explanation reconciling mHA differences observed in HLA-matched DRP.

Bottom Line: All the possible nonameric peptides incorporating the variant amino acid resulting from these SNPs were interrogated in silico for their likelihood to be presented by the HLA class I molecules using the Immune Epitope Database stabilized matrix method (SMM) and NetMHCpan algorithms.A similar library of presented peptides was identified when the data were interrogated using the NetMHCpan algorithm.The bioinformatic algorithm presented here demonstrates that there may be a high level of mHA variation in HLA-matched individuals, constituting a HLA-specific alloreactivity potential.

View Article: PubMed Central - PubMed

Affiliation: Stem Cell Transplant Program, Massey Cancer Center, Virginia Commonwealth University , Richmond, VA , USA.

ABSTRACT
Donor T-cell mediated graft versus host (GVH) effects may result from the aggregate alloreactivity to minor histocompatibility antigens (mHA) presented by the human leukocyte antigen (HLA) molecules in each donor-recipient pair undergoing stem-cell transplantation (SCT). Whole exome sequencing has previously demonstrated a large number of non-synonymous single nucleotide polymorphisms (SNP) present in HLA-matched recipients of SCT donors (GVH direction). The nucleotide sequence flanking each of these SNPs was obtained and the amino acid sequence determined. All the possible nonameric peptides incorporating the variant amino acid resulting from these SNPs were interrogated in silico for their likelihood to be presented by the HLA class I molecules using the Immune Epitope Database stabilized matrix method (SMM) and NetMHCpan algorithms. The SMM algorithm predicted that a median of 18,396 peptides weakly bound HLA class I molecules in individual SCT recipients, and 2,254 peptides displayed strong binding. A similar library of presented peptides was identified when the data were interrogated using the NetMHCpan algorithm. The bioinformatic algorithm presented here demonstrates that there may be a high level of mHA variation in HLA-matched individuals, constituting a HLA-specific alloreactivity potential.

No MeSH data available.


Related in: MedlinePlus