Dynamical system modeling to simulate donor T cell response to whole exome sequencing-derived recipient peptides: Understanding randomness in alloreactivity incidence following stem cell transplantation

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 (pin 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 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.目前尚不明确干细胞移植（stem cell transplant, SCT）供者-受者对（donor-recipient pairs, DRP）中，次要组织相容性抗原（minor histocompatibility antigens, mHA）变异幅度与移植物抗宿主病（graft versus host disease, GVHD）病理生理过程之间的定量关联。为阐明该关联，本研究对27例HLA相合相关供者（HLA matched related, MRD）及50例无关供者（unrelated donors, URD）开展全外显子组测序（whole exome sequencing, WES），以鉴定非同义单核苷酸多态性（nonsynonymous single nucleotide polymorphisms, SNPs）。本研究在MRD组供者-受者对中平均鉴定出2463个SNPs，在URD组中平均鉴定出4287个；随后通过NetMHCpan 2.0软件进行计算机模拟（in silico）预测，并依托GTEx数据库分析上述SNPs编码蛋白的组织表达特征。MRD组供者-受者对平均可产生3670个HLA结合型同种反应性肽段，即推定次要组织相容性抗原（putative mHA, pmHA）；本研究采用算子矩阵构建假想细胞毒性T细胞克隆扩增载体，并通过生长逻辑斯蒂方程计算每种同种反应性T细胞克隆的增殖情况，同时纳入每种肽段的HLA结合亲和力与组织表达特征作为校正参数。由此得到的器官特异性同种反应性T细胞克隆扩增模拟结果显示出显著异质性，不同供者-受者对之间的T细胞数量差异可达数个数量级。尽管本模型为所有供者-受者对统一设定了估算参数，且患者队列接受了异质性治疗方案，但受者体内总T细胞计数及器官特异性T细胞计数越高，其中重度GVHD的累积发病率也越高。综上，每一例供者-受者对的全外显子组序列差异，以及其同种反应性肽段与HLA结合的异质性，均可导致供者T细胞产生跨度极大的同种反应性应答。本研究结果亦有助于阐释同种免疫应答发生过程中所观察到的表观随机性。