Two reports suggest that depletional immunotherapy is less effective in animals with chronic viral infections. Two reports suggest that depletional immunotherapy is less effective in animals with chronic viral infections. CITATION: Wieland A, Shashidharamurthy R, Kamphorst AO, et al. Antibody effector functions mediated by Fcγ-receptors are compromised during persistent viral infection. Immunity 2015; 42: 367–378. CITATION: Yamada DH, Elsaesser H, Lux A, et al. Suppression of Fcγ-receptor-mediated antibody effector function during persistent viral infection. Immunity 2015; 42: 379–390. Fc receptors are a diverse class of molecules that serve to carry out the effector functions of secreted IgG. Ligation of Fcγ receptors (FcγRs) results in activation of macrophages, dendritic cells and natural killer cells, resulting in clearance of antibody-coated targets through mechanisms such as antibody-dependent cellular cytotoxicity (ADCC). Myriad therapeutic strategies have capitalized on this process to remove either large fractions of immune cells from patients (ie, lymphocyte depletion with alemtuzumab) or to target individual cell types via the delivery of antibodies recognizing cell-type–specific antigens (ie, rituximab to target CD20-expressing lymphomas). Factors influencing the effectiveness and completeness of cellular depletion following administration of these reagents can have profound effects on their effectiveness in the treatment of disease. In a pair of papers published in Immunity in 2015, Wieland et al and Yamada et al report on studies in which they had initially attempted to use T cell–depleting therapies in murine recipients that had previously received a chronic viral infection (lymphocytic choriomeningitis virus [LCMV]). To their surprise, experimental T cell depletion (using an anti-CD4 antibody) was much less efficacious in chronically LCMV-infected mice compared with uninfected controls. This phenomenon was not due to an intrinsic inability of T cells from chronically infected mice to be killed, as adoptive transfer into naïve hosts rendered these cells highly susceptible to subsequent antibody-mediated depletion. In addition, this effect was not due to impaired phagocytic ability of macrophages in chronically virally infected animals, as CD11b+ splenocytes of naïve and LCMV clone-13–infected mice showed comparable phagocytic activity in vitro. Instead, the authors used a BCR-transgenic mouse, which possesses an intact B cell compartment but generates antibodies specific only for an irrelevant nonviral antigen, to test the role of viral-specific immune complexes in inhibiting the efficacy of T cell depletion therapy. Intriguingly, chronically infected mice that could not make viral-specific antibodies were much more susceptible to T cell depletion therapy compared with mice that could generate viral-specific antibodies, and the viral-specific antibody titer inversely correlated with the efficacy of T cell depletion in this model. This was true not only for T cell depletion, but also for other Fc-dependent effects of immune therapeutics including the ability of rituximab to deplete hCD20+ B cells and the ability of an agonistic anti-CD40 to activate dendritic cells in vivo. The implications of this work for the field of transplantation are apparent. First, the data suggest that patients with chronic viral infections such as human immunodeficiency and hepatitis C viruses may be more resistant to depletional induction therapy at the time of transplantation. Furthermore, it is possible that reactivation of certain viruses, Epstein–Barr virus in particular due to its well-appreciated ability to induce high levels of serum IgG, may interfere with Fc-containing strategies to treat episodes of acute rejection posttransplant (ie, thymoglobulin). In addition to the potential impact of virus-specific antibodies on the efficacy of depletional therapy for transplantation, it is also interesting to speculate that high levels of antidonor antibody could similarly limit the effectiveness of Fc-active biologics for use in transplantation at any stage. Overall, the discovery that chronic, high levels of immune complexes can impair the effectiveness of immunotherapy provides further impetus for the engineering of Fc-modified reagents that possess higher affinity for activating FcγRs, and may thus be able to outcompete endogenous immune complexes for access to the receptors and provide superior efficacy in vivo. Dr. Ford is associate professor at the Emory Transplant Center at Emory University School of Medicine in Atlanta. She is also section editor for “Literature Watch.”
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Sep 19, 2017
Masahito Munakata + 5
Open Access