Interferon-α and its effects on post-transplant lymphoproliferative disorders

Abstract

EBV-transformation induces B lymphocytes to secrete high levels of human IL-10. Additionally, EBV contains a gene, BCRF1, that encodes for a protein that shares activity with human IL-10 in vitro. Thus, infection by EBV seems to promote a Th2 environment in the infected host. One may even hypothesize that EBV-derived IL-10 initiates a cascade of events that promotes a Th2 response and suppresses Th1 activity. This is further confirmed by data that suggest elevated concentrations of IL-4, IL-10, and IgE in patients with PTLD. This implies an association between PTLD and an imbalance in the immunoregulatory system with either an excess suppression of Th1 cells and/or an up-regulation of Th2 cells. One could speculate that if the imbalance in the immunoregulatory system is corrected, the patient's own immune system could potentially defend itself against the virus. Clearly, this is the case in those immunocompromised patients with PTLD who respond to just a reduction in their immunosuppression. Unfortunately, this is only beneficial in approximately half of patients with PTLD. Perhaps this is because patients often do not become entirely immunocompetent, either because all of their immunosuppression cannot be discontinued for fear of rejection or because once the above cascade is established the immune system is not capable of easily switching to the Th1 response necessary for combating the virus. Theoretically, IFN-alpha, because of its anti-viral effect, its anti-neoplastic effect and/or possibly by its ability to promote a Th1 response, should be useful in the treatment of PTLD. IFN-alpha modulates the immune system by several mechanisms including: preventing B cells from producing immunoglobulins, reducing IL-6 receptor density, and augmenting the inhibition of IL-4 by IL-12. In vitro studies document its effectiveness against EBV. Unfortunately, the available evidence as to its efficacy in vivo in patients with PTLD is very limited. At present, there are only 16 reported cases in the literature. There are also three cases of BLPD in immunocompromised patients that were all successfully treated with IFN-alpha and the two cases alluded to earlier from Children's Hospital of Pittsburgh (personal communication). Although the numbers are small, the results are promising. Of the 21 patients with BLPD who received IFN-alpha, 15 achieved complete remission. Four others improved and 2 died from BLPD. One of the 4 that improved died 3 months later from a relapse. Thus, there was an overall mortality of 14% (3 of 21) in those who received therapy with IFN-alpha. This is a very heterogeneous group of patients, several of whom had also received additional therapies. Thus, it is impossible to draw definitive conclusions. However, the mortality rate in this group of patients, who had already failed therapy with a reduction in their immunosuppression, compares very favorably to the reported mortality rate of approximately 23-81% in patients with PTLD. This data suggest that a large multi-centered prospective trial comparing IF...

Identifying the patient at risk for post‐transplant lymphoproliferative disorder

“…These data suggest that the cytokine profile generated in response to EBV may influence the outcome of infection. The manipulation of cytokine gene expression away from the Th2 pattern of IL‐4 and IL‐10 production may explain some of the therapeutic benefits described in patients with PTLD treated with interferon‐α (39). It remains uncertain whether such strategies can be exploited in prophylaxis protocols in patients at high risk of PTLD.…”

Immunotherapeutic options for Epstein–Barr virus-associated lymphoproliferative disease following transplantation

“…While IFN-α therapy can induce regression of polyclonal EBV-LPD, it is associated with a high risk of graft rejection [81,100]. IL-6, a pleiotropic cytokine, is an autocrine growth factor for the proliferation of EBV-infected B cells.…”