Genetic variations in T-cell activation and effector pathways modulate alloimmune responses after allogeneic hematopoietic stem cell transplantation in patients with hematologic malignancies.

Abstract

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.

DESIGN AND 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.

• Authors: Haowen Xiao, Yi Luo, Xiaoyu Lai, Shan Fu, Jimin Shi, Yamin Tan, Jingsong He, Wanzhuo Xie, Weiyan Zheng, Li-Mengmeng Wang, Lifei Zhang, Lizhen Liu, Xiujin Ye, Xiaohong Yu, Zhen Cai, Maofang Lin, He Huang
• Journal: Haematologica (Haematologica) Vol. 97 Issue 12 Pg. 1804-12 (Dec 2012) ISSN: 1592-8721 [Electronic] Italy
• PMID: 22733023 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD28 Antigens
• CTLA-4 Antigen
• FAS protein, human
• Fas Ligand Protein
• ICOS protein, human
• Inducible T-Cell Co-Stimulator Protein
• fas Receptor
• Granzymes

Topics

• Adolescent
• Adult
• CD28 Antigens (genetics)
• CTLA-4 Antigen (genetics)
• Child
• Cohort Studies
• Fas Ligand Protein (genetics)
• Female
• Follow-Up Studies
• Graft vs Host Disease
• Granzymes (genetics)
• Hematologic Neoplasms (etiology, mortality, therapy)
• Hematopoietic Stem Cell Transplantation
• Humans
• Immunity, Cellular
• Inducible T-Cell Co-Stimulator Protein (genetics)
• Lymphocyte Activation
• Male
• Middle Aged
• Neoplasm Recurrence, Local (etiology, mortality, therapy)
• Polymerase Chain Reaction
• Polymorphism, Single Nucleotide (genetics)
• Prognosis
• Risk Assessment
• Siblings
• Survival Rate
• T-Lymphocytes (immunology)
• Tissue Donors
• Transplantation, Homologous
• Young Adult
• fas Receptor (genetics)