Integrated Immunologic Monitoring in Solid Organ Transplantation: The Road Toward Torque Teno Virus-guided Immunosuppression

Abstract

Potent immunosuppressive drugs have been introduced into clinical care for solid organ transplant recipients. It is now time to guide these drugs on an individual level to optimize their efficacy. An ideal tool simultaneously detects overimmunosuppression and underimmunosuppression, is highly standardized, and is straightforward to implement into routine. Randomized controlled interventional trials are crucial to demonstrate clinical value. To date, proposed assays have mainly focused on the prediction of rejection and were based on the assessment of few immune compartments. Recently, novel tools have been introduced based on a more integrated approach to characterize the immune function and cover a broader spectrum of the immune system. In this respect, the quantification of the plasma load of a highly prevalent and apathogenic virus that might reflect the immune function of its host has been proposed: the torque teno virus (TTV). Although TTV control is driven by T cells, other major immune compartments might contribute to the hosts' response. A standardized in-house polymerase chain reaction and a conformité européenne-certified commercially available polymerase chain reaction are available for TTV quantification. TTV load is associated with rejection and infection in solid organ transplant recipients, and cutoff values for risk stratification of such events have been proposed for lung and kidney transplantation. Test performance of TTV load does not allow for the diagnosis of rejection and infection but is able to define at-risk patients. Hitherto TTV load has not been used in interventional settings, but two interventional randomized controlled trials are currently testing the safety and efficacy of TTV-guided immunosuppression.

Graphical abstract

FIGURE 1.

The hosts’ plasma torque teno virus (TTV) load in relation to the risk of allograft rejection and infection in kidney (KTX) and lung transplant (LuTX) recipients. A high TTV load indicates a risk of infection, and a low TTV load indicates a risk of rejection. Proposed cutoff values for risk stratification have been converted to values that correspond to the commercial polymerase chain reaction (PCR) to facilitate comparison of the published data. The risk for infection increases above 6.6 log10 c/mL for both KTX and LuTX recipients. For KTX patients, the risk for rejection increases at TTV loads below 4.6 log10 c/mL. The field including an asterisk represents TTV loads below 5.6 log10 c/mL, which already indicate a risk in the LuTX setting due to the higher level of immunosuppression needed to prevent rejection compared with KTX. In KTX recipients transplanted >1 y ago, a TTV load above 3.6 log10 c/mL might indicate sufficient immunosuppression to prevent rejection (double asterisk).