Genetic variations in T-cell activation and effector pathways modulate alloimmune responses after allogeneic hematopoietic stem cell transplantation in patients with hematologic malignancies.
BACKGROUND
Recently, several important polymorphisms have been identified in T-cell activation and effector pathway genes and have been reported to be associated with inter-patient variability in alloimmune responses. The present study was designed to assess the impact of these genetic variations on the outcomes of allogeneic hematopoietic stem cell transplantation.


METHODS
We first investigated ten single nucleotide polymorphisms in six genes, CD28, inducible co-stimulator, cytotoxic T-lymphocyte antigen 4, granzyme B, Fas and Fas ligand, in 138 pairs of patients and their unrelated donors and a second cohort of 102 pairs of patients and their HLA-identical sibling donors.


RESULTS
We observed that patients receiving stem cells from a donor with the cytotoxic T-lymphocyte antigen 4 gene CT60 variant allele (AA genotype) had a reduced incidence of grades II-IV acute graft-versus-host disease; however, they experienced early cytomegalovirus infection and relapsed more frequently, which suggested an interaction between the donor cytotoxic T-lymphocyte antigen 4 gene CT60 AA genotype and reduced T-cell alloreactivity. Furthermore, an unrelated donor with the granzyme B +55 variant genotype (AA) was an independent risk factor for development of grades II-IV acute graft-versus-host disease (P=0.024, RR=1.811). Among patients with acute myelogenous leukemia, those with the Fas -670 TT genotype were at higher risk of relapse (P=0.003, RR=3.823). The presence of these susceptible alleles in the donor and/or patient resulted in worse overall survival (54.9% versus 69.5%, P=0.029).


CONCLUSIONS
Our data suggest that genotype analysis of T-cell activation and effector pathway genes can be used for risk assessment for patients with hematologic malignancies before hematopoietic stem cell transplantation.
Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, PR China.
Haowen
H
Xiao
Yi
Y
Luo
Xiaoyu
X
Lai
Shan
S
Fu
Jimin
J
Shi
Yamin
Y
Tan
Jingsong
J
He
Wanzhuo
W
Xie
Weiyan
W
Zheng
Li-Mengmeng
LM
Wang
Lifei
L
Zhang
Lizhen
L
Liu
Xiujin
X
Ye
Xiaohong
X
Yu
Zhen
Z
Cai
Maofang
M
Lin
He
H
Huang
D000293:Adolescent; D000328:Adult; D018106:CD28 Antigens / Q000235:genetics; D060908:CTLA-4 Antigen / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D053222:Fas Ligand Protein / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease; D053804:Granzymes / Q000235:genetics; D019337:Hematologic Neoplasms / Q000209:etiology* / Q000401:mortality / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007111:Immunity, Cellular; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000209:etiology* / Q000401:mortality / Q000628:therapy; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D018570:Risk Assessment; D035781:Siblings; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology*; D014019:Tissue Donors; D014184:Transplantation, Homologous; D055815:Young Adult; D019014:fas Receptor / Q000235:genetics
D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C491901:FAS protein, human; D053222:Fas Ligand Protein; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D019014:fas Receptor; D053804:Granzymes