Introduction of mTor Inhibitors and the Activation of the Cytomegalovirus (CMV) -Specific Cellular Immune Response

Overview

Kidney transplant patients under an immunosuppressive treatment based on anti-calcineurin and mycophenolate-mofetil and induction therapy with rATG who suffer from early systemic viral replication by the CMV virus could benefit from the introduction of an i-mTor drug. (everolimus) to replace mycophenolate mofetil. This conversion would be effective in slowing down and controlling viral expansion without the need to initiate any prophylactic anti-viral therapy thanks to the activation of the CMV-specific cellular effector response or to an antiviral effect of i-Mtor itself.

Human cytomegalovirus (CMV) is the most common opportunistic pathogen in the first months after solid organ transplantation, being associated with an increased risk of acute and chronic graft rejection, graft loss and an increase in patient mortality. The susceptibility to developing CMV infection is essentially determined by the host's immune status against the virus, with seronegative recipients (IgG-) receiving a graft from a seropositive donor (IgG +) (R- / D +) being the group with an especially high risk of developing CMV infection and disease after transplantation. In fact, without the administration of a preventive therapy for CMV, around 60-70% of this risk group will present viral infection (replication of copies of CMV in blood) and up to 30% will develop systemic disease (viral invasion of the tissue). However, the incidence of infection among R + / D + seropositive (IgG +) patients under treatment with induction with anti-IL2RA and the combination of mycophenolate mofetil (MPA) and anti-calcineurin drugs (CNI), can reach up to 40%, and up to 60% if induction therapies are administered with T-lymphocyte depletors with polyclonal antibodies (Thymoglobulin®, rATG) (6). All this suggests that the assessment of the immunological risk of developing post-transplant CMV infection is relatively poor and that the humoral response to the virus does not fully explain the patient's immunological susceptibility to the virus. In this sense, it is well known that the subpopulation of CMV-specific memory / effector T cells plays a key role in the control of viral survival replication in general and of CMV in particular. While it has been reported that CD8 + cytotoxic T cells have the ability to activate against a wide range of immunogenic proteins of the CMV virus, it appears that high frequencies directed against the major CMV antigens such as those of immediate expression-1 (IE-1) and phosphoprotein 65 (pp65) play a critical role in the control of CMV viral replication. One of the most precise functional techniques to study the cellular memory immune response is the IFN-γ ELISPOT test, which allows knowing the antigen-specific response at the individual cellular level, thus providing high sensitivity and specificity. Along these lines, our group and others have shown how the monitoring of the CMV-specific cell response with the IFN-γ ELISPOT test, both before and after transplantation, is capable of identifying those patients with a high risk of developing infection by CMV, regardless of immunization status. In addition, data from a prospective, randomized clinical trial led by our group, evaluating the cellular response to CMV before transplantation using the IFN-γ ELISPOT test, have confirmed the high negative predictive power in identifying those patients with high risk of developing viral infection after transplantation, despite being serologically positive. Mtor (mammalian target of rapamycin) inhibitors, everolimus and sirolimus, are a class of immunosuppressants commonly used in kidney transplantation both in the initial phase (de novo) and in the maintenance phase. In addition, today it is considered routine clinical practice in case of side effects mediated by CNI (tacrolimus or cyclosporine) or by antimetabolites (mycophenolate mofetil or mycophenolic acid) to replace the latter with iMtor (conversion to iMtor). Interestingly, recently reported clinical studies have shown a significant decrease in the rate of both CMV infection and disease in patients treated with mTor inhibitors (i-mTOR) after kidney transplantation, both in combination with MPA. as in combination with CNI drugs. A recently published randomized clinical trial that included more than 2000 kidney transplant patients has reported that the incidence of CMV viral infection in the CNI plus everolimus group in the Serology D / R + / + group was 3.6% compared to 13.3% of the control group treated with CNI plus mycophenolate mofetil. (RR 0.27 - CI 0.19-0.38) This effect has been reported mainly among R + / D + patients, and even in those after receiving induction treatment with rATG. Although the mechanism through which i-mTORs can inhibit and block viral replication after transplantation is unknown, it is suggested that it could be through their ability to directly inhibit proliferation on the virus, or well, through some of the immunomodulatory pleiotropic effects that they exert on the adaptive immune response. Along these lines, beyond its immunosuppressive capacity by inhibiting the lymphocyte proliferation signal

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