Published online Sep 28, 2017. doi: 10.4254/wjh.v9.i27.1115
Peer-review started: February 8, 2017
First decision: March 27, 2017
Revised: April 6, 2017
Accepted: June 12, 2017
Article in press: June 13, 2017
Published online: September 28, 2017
To investigate the role of glutathione S-transferase T1 donor-specific T lymphocytes in plasma cell-rich rejection of liver allografts.
The study group included 22 liver transplant patients. Among them, 18 patients were mismatched for the glutathione S-transferase T1 (GSTT1) alleles (don+/rec-), and 4 were matched (don+/rec+). Seven of the mismatched patients produced anti-GSTT1 antibodies and developed plasma cell-rich rejection (former de novo immune hepatitis). For the detection of specific T lymphocytes, peripheral blood mononuclear cells were collected and stored in liquid nitrogen. The memory T cell response was studied by adding to the cell cultures to a mix of 39 custom-made, 15-mer overlapping peptides, which covered the entire GSTT1 amino acid sequence. The specific cellular response to peptides was analyzed by flow cytometry using the markers CD8, CD4, IL-4 and IFNγ.
Activation of CD8+ T cells with different peptides was observed exclusively in the group of patients with plasma-cell rich rejection (3 out of 7), with production of IL-4 and/or IFNγ at a rate of 1%-4.92% depending on the peptides. The CD4+ response was most common and not exclusive for patients with the disease, where 5 out of 7 showed percentages of activated cells from 1.24% to 31.34%. Additionally, two patients without the disease but with the mismatch had cells that became stimulated with some peptides (1.45%-5.18%). Highly unexpected was the finding of a double positive CD4+CD8low T cell population that showed the highest degree of activation with some of the peptides in 7 patients with the mismatch, in 4 patients with plasma cell-rich rejection and in 3 patients without the disease. Unfortunately, CD4+CD8low cells represent 1% of the total number of lymphocytes, and stimulation could not be analyzed in 9 patients due to the low number of gated cells. Cells from the 4 patients included as controls did not show activation with any of the peptides.
Patients with GSTT1 mismatch can develop a specific T-cell response, but the potential role of this response in the pathogenesis of plasma cell-rich rejection is unknown.
Core tip: In solid organ transplants, donor recipient mismatch of glutathione S-transferase T1 (GSTT1) alleles triggers a specific immune response with the production of IgG antibodies. In a proportion of mismatched liver and kidney transplants, the clinical outcome is rejection. However, detection of GSTT1-specific T lymphocytes has not been documented. We provide the first evidence of T cells able to become activated by GSTT1 peptides in patients who develop plasma cell-rich (PC-rich) rejection after GSTT1-mismatch liver transplantation. Interestingly, not only CD8+ or CD4+ cells but also double positive CD4+CD8low cells reacted to the antigenic stimulation in vitro.