CD28 expression by peripheral blood lymphocytes as a potential predictor of the development of de novo malignancies in long-term survivors after liver transplantation

Abstract

At present, no method is available for accurately monitoring the degree of immunosuppression induced by antirejection therapies. The aim of this study was to determine whether CD28 and CD38 expression by peripheral blood mononuclear cells could be useful in predicting the development of de novo malignancies after liver transplantation. Flow cytometry analysis was used to measure the expression of CD28 and CD38 by peripheral blood lymphocytes in 134 stable, long-term survivors of liver transplantation. Patients who developed a de novo malignancy after undergoing a medical checkup were entered into a cancer group. Twenty-two patients (16.4%) developed at least 1 de novo malignancy over a mean interval of 22 6 14 months (1.2-49.4 months) after the checkup. The mean frequency of CD28 þ CD8 þ cells was significantly lower in the cancer group versus the noncancer group (39% 6 22 versus 51% 6 21, P ¼ 0.008), but CD38 expression was similar in the 2 groups. Multivariate analysis indicated that an age greater than 50 years (odds ratio ¼ 5.81) and a low frequency of CD28 þ CD8 þ cells at the time of the checkup (odds ratio ¼3.16) were the only significant predictors of the development of de novo malignancies (P ¼ 0.027). The actuarial proportion of patients with de novo malignancies was significantly lower when the frequency of CD28 þ CD8 þ cells was greater than or equal to 40% instead of less than 40% (P ¼ 0.01). Flow cytometry measurements of CD28 expression by peripheral blood lymphocytes may facilitate the identification of patients at a high risk of developing de novo malignancies. Further prospective studies are necessary to determine whether such measurements could have a place in routine clinical practice to enable the intensity of immunosuppression to be minimized in patients who have an increased risk of developing cancer.

Lymphocyte surface molecules as immune activation biomarkers

“…Wieland and Shipkova, Lymphocyte surface molecules 7 transplantation is very limited and, as mentioned above, the patient cohorts that are included are small. Table 1 summarizes the studies and markers that were used in clinical trials that aimed at outcome measurements.…”

“…An interesting concept is to use donor-specific peptides that are presented to the recipient T cells semi-directly through antigen presenting cells. For the assessment of CD28, CD26 and CD95 (FasL) on the cell surface of T cells, normally no ex vivo stimulation step is required [7][8][9]. The specific and non-specific can be anticipated that standardization of methods for measuring less well characterized biological macro molecules such as the surface antigens is a very challenging task.…”

“…Interestingly, this surface marker was also helpful as an indicator of over-immunosuppression because in patients 4.4 ± 3.1 years after liver transplantation, a low frequency of CD8 T cells expressing CD28 was related to malignancy incidence (21 solid tumors and 1 lymphoproliferative disorder) within 22 ± 14 months after the surface marker expression assessments [7]. CD28 expression on CD3 cells was able to separate activated T cells in liver transplant patients due to acute rejection episodes from activation that was caused by concurrent hepatitis B or C infection compared with non-rejecting patients [9].…”

Biomarkers in blood for individualization of the pharmacotherapy with immunosuppressive drugs after transplantation of solid organs

“…In contrast to the complicated cell function assays using ex vivo stimulation, the measurement of CD26 on CD3 cells directly in whole blood seems to allow for a statement about the degree of activation of the T-cells in vivo. Boleslawski et al report, in connection with liver transplantation, that CD28 on CD8 cells can be associated with both rejections in the early phase after transplantation (many CD28/CD8 cells) and tumor diseases over the long term (few CD28/ CD8 cells) [39,40] .…”

Biomarkers

“…Boleslawski et al reported an association between a decreased level of CD28 expression on CD8 þ cells and malignancies in long-term liver transplant patients, as well as an association between increased expression and rejection [84,85]. So far, no standardization of assay protocols has been achieved and no sound data from larger clinical trials have been published.…”