Alexandre Iannello

Role of antibody-dependent cell-mediated cytotoxicity in the efficacy of therapeutic anti-cancer monoclonal antibodies

SummaryIn recent years, interest in anti-cancer therapeutic monoclonal antibodies (mAb) has been renewed. Several of these reagents have been approved for therapy in a variety of cancer patients and many others are in different stages of development. It is believed that multiple mechanisms are involved in the anti-cancer effects of these reagents. However, several in vitro and in vivo studies have demonstrated that antibody-dependent cell-mediated cytotoxicity (ADCC) is their predominant mode of action against cancer cells. The requirement for a direct interaction between mAb and receptors for the Fc region of the antibodies (FcR) has been demonstrated for anti-tumor effects of these antibodies. Consequently, FcR-bearing immune effector cells play an important role in mediating their effects. It is not surprising that cancer cells have developed different strategies to evade these antibodies. Several strategies are proposed to potentiate the mAb-mediated ADCC in cancer patients. They may enhance anti-cancer therapeutic effects of these regents.

HIV-Specific IL-21 Producing CD4+ T Cells Are Induced in Acute and Chronic Progressive HIV Infection and Are Associated with Relative Viral Control

We examined the role of CD4+ T cell IL-21 production in viral control of HIV infection. HIV-infected individuals had greater circulating IL-21–producing CD4+ T cells in blood compared with uninfected volunteers. HIV-specific IL-21–producing CD4+ T cells were detected in blood during untreated acute and chronic HIV infection, and elevated frequencies of these cells correlated with relative viral control. These cells had an effector memory or end effector phenotype and expressed CXCR5. HIV-specific CD8+ T cells exhibited high levels of IL-21R, indicating sensitivity to IL-21. Low or aviremic long-term nonprogressors, however, showed absent or low HIV-specific IL-21 CD4+ T cells, but more easily detectable HIV-specific IL-2–producing CD4+ T cells, suggesting changing requirements for particular γ-chain cytokines depending on Ag abundance. Thus, IL-21–producing CD4+ T cells are induced in viremic HIV infection and likely contribute to viral control by affecting CD8+ T cell maintenance.

Antiviral NK cell responses in HIV infection: I. NK cell receptor genes as determinants of HIV resistance and progression to AIDS

NK cells play an important role in controlling viral infections. They can kill virus‐infected cells directly as well as indirectly via antibody‐dependent, cell‐mediated cytotoxicity. They need no prior sensitization and expansion for this killing. NK cells are also considered as important regulators of antiviral immune responses. They do so by secreting a multitude of soluble mediators and by directly interacting with other immune cells, e.g., dendritic cells. NK cells do not possess a single well‐defined receptor to recognize antigens on target cells. Instead, they express an array of inhibitory and activating receptors and coreceptors, which bind to their cognate ligands expressed on the surface of target cells. These ligands include classical and nonclassical MHC class I antigens, MHC‐like proteins, and a variety of other self‐ and virus‐derived molecules. They may be expressed constitutively and/or de novo on the surface of virus‐infected cells. NK cell receptors (NKRs) of the killer‐cell Ig‐like receptor (KIR) family, like their MHC class I ligands, are highly polymorphic. Several recent studies suggest that epistatic interactions between certain KIR and MHC class I genes may determine innate resistance of the host to viral infections, including HIV. In the first part of this review article, we provide an overview of the current state of knowledge of NK cell immunobiology and describe how NKR genes, alone and in combination with HLA genes, may determine genetic resistance/susceptibilty to HIV infection and the development of AIDS in humans.

Viral strategies for evading antiviral cellular immune responses of the host

The host invariably responds to infecting viruses by activating its innate immune system and mounting virus‐specific humoral and cellular immune responses. These responses are aimed at conrolling viral replication and eliminating the infecting virus from the host. However, viruses have evolved numerous strategies to counter and evade hosts antiviral responses. Providing specific examples from the published literature, we discuss in this review article various strategies that viruses have developed to evade antiviral cellular responses of the host. Unraveling these viral strategies allows a better understanding of the host‐pathogen interactions and their coevolution. This knowledge is important for identifying novel molecular targets for developing antiviral reagents. Finally, it may also help devise new knowledge‐based strategies for developing antiviral vaccines.

Decreased levels of circulating IL-21 in HIV-infected AIDS patients: Correlation with CD4+ T-cell counts

IL-21 is a relatively newly discovered multifunctional and pleiotropic cytokine. It is produced primarily by CD4(+) T cells, the principal targets of the virus, and therefore this cytokine has special relevance to HIV infection. Here we show for the first time that serum levels of this cytokine are significantly reduced in HIV-infected AIDS patients and correlate significantly with their CD4(+) T-cell counts. These data suggest that the cytokine levels could act as a valuable biomarker for the progression of AIDS.

Antiviral NK cell responses in HIV infection: II. viral strategies for evasion and lessons for immunotherapy and vaccination

As is the case in other viral infections, humans respond to HIV infection by activating their NK cells. However, the virus uses several strategies to neutralize and evade the host’s NK cell responses. Consequently, it is not surprising that NK cell functions become compromised in HIV‐infected individuals in early stages of the infection. The compromised NK cell functions also adversely affect several aspects of the host’s antiviral adaptive immune responses. Researchers have made significant progress in understanding how HIV counters NK cell responses of the host. This knowledge has opened new avenues for immunotherapy and vaccination against this infection. In the first part of this review article, we gave an overview of our current knowledge of NK cell biology and discussed how the genes encoding NK cell receptors and their ligands determine innate genetic resistance/susceptibilty of humans against HIV infections and AIDS. In this second part, we discuss NK cell responses, viral strategies to counter these responses, and finally, their implications for anti‐HIV immunotherapy and vaccination.

Novel associations between activating killer-cell immunoglobulin-like receptor genes and childhood leukemia

Acute lymphoblastic leukemia of pre-B cells (pre-B ALL) is the most frequent form of leukemia affecting children in Western countries. Evidence is accumulating that genetic factors play an important role in conferring susceptibility/resistance to leukemia in children. In this regard, activating killer-cell immunoglobulin-like receptor (KIR) genes are of particular interest. Humans may inherit different numbers of the 6 distinct activating KIR genes. Little is known about the impact of this genetic variation on the innate susceptibility or resistance of humans to the development of B-ALL. We addressed this issue by performing a case-control study in Canadian children of white origin. Our results show that harboring activating KIR genes is associated with reduced risk for developing B-ALL in these children. Of the 6 activating KIR genes, KIR2DS2 was maximally associated with decreased risk for the disease (P = 1.14 × 10(-7)). Furthermore, our results showed that inheritance of a higher number of activating KIR genes was associated with significant reductions in risk for ALL in children. These results were also consistent across different ALL phenotypes, which included children with pre-T cell ALL. Our study provides novel insights concerning the pathogenesis of childhood leukemia in white children and has implications for the development of new immunotherapies for this cancer.

Regulation of Phagocytosis in Macrophages by Neuraminidase 1

The differentiation of monocytes into macrophages and dendritic cells is accompanied by induction of cell-surface neuraminidase 1 (Neu1) and cathepsin A (CathA), the latter forming a complex with and activating Neu1. To clarify the biological importance of this phenomenon we have developed the gene-targeted mouse models of a CathA deficiency (CathAS190A) and a double CathA/Neu1 deficiency (CathAS190A-Neo). Macrophages of CathAS190A-Neo mice and their immature dendritic cells showed a significantly reduced capacity to engulf Gram-positive and Gram-negative bacteria and positively and negatively charged polymer beads as well as IgG-opsonized beads and erythrocytes. Properties of the cells derived from CathAS190A mice were indistinguishable from those of wild-type controls, suggesting that the absence of Neu1, which results in the increased sialylation of the cell surface proteins, probably affects multiple receptors for phagocytosis. Indeed, treatment of the cells with purified mouse Neu1 reduced surface sialylation and restored phagocytosis. Because Neu1-deficient cells showed reduced internalization of IgG-opsonized sheep erythrocytes whereas binding of the erythrocytes to the cells at 4 °C persisted, we speculate that the absence of Neu1 in particular affected transduction of signals from the Fc receptors for immunoglobulin G (FcγR). Indeed the macrophages from the Neu1-deficient mice showed increased sialylation and impaired phosphorylation of FcγR as well as markedly reduced phosphorylation of Syk kinase in response to treatment with IgG-opsonized beads. Altogether our data suggest that the cell surface Neu1 activates the phagocytosis in macrophages and dendritic cells through desialylation of surface receptors, thus, contributing to their functional integrity.

IL-15 and HIV Infection: Lessons for Immunotherapy and Vaccination

IL-15 is a pleiotropic and multifunctional cytokine that has a diverse array of distinct biological effects in the body. It plays a crucial role in host defense from viral and non-viral intracellular pathogens. The cytokine is essential for the development and differentiation of NK cells and for homeostatic expansion of CD8+ memory T cells, NKT cells and certain subsets of intestinal intra-epithelial lymphocytes (iIEL). It acts as a survival factor and inhibits spontaneous apoptosis in T, B and NK cells by increasing expression of different anti-apoptotic proteins. Several studies have shown that IL-15 production is compromised in HIV-infected AIDS patients and exogenous IL-15 drastically enhances functions of immune cells from these patients. Considering these distinct immune enhancing effects, relative safety in animal models, and minimal effects on HIV replication, IL-15 may represent a better cytokine for immune reconstitution in these patients. Furthermore, IL-15 may also act as a better adjuvant in eliciting antiviral immunity in anti-HIV vaccine strategies.

IL‐21 enhances NK cell functions and survival in healthy and HIV‐infected patients with minimal stimulation of viral replication

IL‐21 plays an important role in regulating immune response and controlling chronic viral infections. Recently, we reported its decreased serum concentrations and their immunological consequences in HIV‐infected persons. In this study, we have investigated how exogenous IL‐21 enhances NK cell responses in these persons. We show that the cytokine receptors are expressed equally on all NK cell subsets defined by expression of CD16 and CD56; the cytokine activates STAT‐3, MAPK, and Akt to enhance NK cell functions; the STAT‐3 activation plays a key role in constitutive and IL‐21‐mediated enhancement of NK cell functions; the cytokine increases expression of antiapoptotic proteins Bcl‐2 and Bcl‐XL and enhances viability of NK cells but has no effect on their proliferation; the cytokine enhances HIV‐specific ADCC, secretory, and cytotoxic functions, as well as viability of NK cells from HIV‐infected persons; it exerts its biological effects on NK cells with minimal stimulation of HIV‐1 replication; and the cytokine‐activated NK cells inhibit viral replication in cocultured, HIV‐infected, autologous CD4+ T cells in a perforin‐ and LFA‐1‐dependent manner. These data suggest that IL‐21 may serve as a valuable therapeutic tool for enhancing NK cell responses and inhibiting viral replication in HIV‐infected patients.