Use of T Cell Mediated Immune Functional Assays for Adjustment of Immunosuppressive or Anti-infective Agents in Solid Organ Transplant Recipients: A Systematic Review

Abstract

Background: Defining the optimal dosage of the immunosuppressive or duration of anti-infective agents is a challenge in solid organ transplant (SOT) recipients. We aimed to systematically review the literature regarding the use of T cell mediated immune functional assays (IFAs) for adjustment of the immunosuppressive or anti-infective agents in SOT recipients. Methods: We systematically searched PubMed, Scopus, EMBASE, Web of Science (WOS), Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov to find human interventional studies or study protocols that used either in-house or commercially available IFAs for adjustment of the immunosuppressive or anti-infective agents in SOT recipients. Results: We included six clinical trials and six study protocols. Four out of the six clinical trials used interferon-γ release assays for cytomegalovirus (IGRA-CMV), and five out of the six registered study protocols planned to use IGRA-CMV for adjustment of anti-CMV antiviral (Valganciclovir) prophylaxis or preemptive therapy in SOT recipients. Primary or secondary anti-CMV prophylaxes were discontinued in SOT recipients who had positive IGRA-CMV results without an increase in the rate of CMV infection or reactivation. Among other IFAs, one clinical trial used interferon-γ release assays for tuberculosis (IGRA-TB), and one study used ImmuKnow for adjustment of the duration and dosage of isoniazid and tacrolimus, respectively. Conclusion: Our systematic review supports a promising role for the IGRA-CMVs for adjustment of the duration of anti-CMV antiviral prophylaxis in SOT recipients. There are limited data to support the use of IFAs other than IGRA-CMVs for adjustment of immunosuppressive or anti-infective agents. Further multicenter randomized clinical trials using IFAs other than IGRA-CMVs may help in personalized immunosuppressive or prophylactic anti-infective therapy in SOT recipients.

Keywords: anti-infective agent; immune functional assay; immune system; immunosuppressive agent; transplantation.

Figure 1

In ImmuKnow assay, a sample of whole blood is incubated with phytohemagglutinin (PHA) for 15–18 h. PHA stimulates lymphocytes and lymphocytes including CD4+ T lymphocytes produce adenosine triphosphate (ATP). Anti-CD4 antibodies attached to magnetic particles are added and attach to CD4+ T lymphocytes. CD4+ T lymphocytes are purified and after washing, are lysed. A luminescence reagent (a mixture of luciferin and luciferase) is added. ATP activates luciferase and this enzyme cut luciferin which results in light production. The produced light is measured using the bioluminescence method and reported in nanograms per milliliter (ng/ml). The figure designed by authors using Gravit Designer.

Figure 2

The Interferon-Gamma Release Assays (IGRAs) is performed according to two different methods. In the QuantiFERON, whole blood is incubated with specific antigens overnight (16–24 h). Antigens stimulate lymphocytes and sensitized lymphocytes release interferon-gamma. The interferon-gamma is measured using an enzyme linked immunosorbent assay (ELISA) and is reported as international units (IU) per milliliter. In the T-Track or T.SPOT assay peripheral blood mononuclear cell (PBMC) purified from whole blood are incubated with specific antigens overnight, and sensitized PBMCs release interferon-gamma. The interferon-gamma is measured using an enzyme-linked immunosorbent spot (ELISPOT) and is reported as the number of the formed spots on the ELISPOT's plate. The figure designed by authors using Gravit Designer.

Figure 3

PRISMA flow diagram for the included studies.

Figure 4

(A) Traffic light plots; (B) weighted bar plots for randomized clinical trials. The overall risk of bias was with some concerns for 2 out of 4 randomized clinical trials. The other 2 randomized clinical trials had a high risk of bias.

Figure 5

(A) Traffic light plots; (B) weighted bar plots for non-randomized clinical trials. One of the non-randomized clinical trials had a serious overall risk of bias and the other one had a moderate risk of bias.