Immunomodulatory Mechanisms of Intravenous Immunoglobulin

__Abstract__ Immunity originates from the Latin term immunis, meaning “exempt”, which refers to all the mechanisms used by the body as protection against invasion by agents that are foreign to the body. These agents may be infectious pathogens, foods, chemicals, drugs, and, in terms of transplantation, organ grafts from another individual (allograft). The immune system consists of two functionally distinct arms: the innate immunity arm and the adaptive immunity arm. The innate immunity refers to all those elements with which an individual is born and that are always present and available at short term to protect the individual from challenges by foreign invaders. This response is nonspecific and occurs rapidly upon ligation to innate immune receptors (e.g. Toll-like receptors or C-type lectin receptors). The cell types expressing these receptors and hence participate in the cellular innate immune response include dendritic cells (DCs), macrophages, e.g. Kupffer cells and splenic macrophages, granulocytes and natural killer (NK) cells. A fundamental defense mechanism carried out by these cells is phagocytosis, but also production of cytokines to affect other cells, or release of perforin/granzyme for extracellular killing. In humoral innate immunity, the complement system is the main component. Specific activation of complement by pathogens leads to a cascade of proteolytic reactions that coats pathogens with complement fragments. Complement-coated pathogens are recognized and bound by specific complement receptors on macrophages, taken up by phagocytosis, and destroyed

Differences in anti-inflammatory actions of intravenous immunoglobulin between mice and men: More than meets the eye

Intravenous immunoglobulin (IVIg) is a therapeutic preparation of polyspecific human IgGs purified from plasma pooled from thousands of individuals. When administered at a high dose, IVIg inhibits inflammation and has proven efficacy in the treatment of various autoimmune and systemic inflammatory diseases. Importantly, IVIg therapy can ameliorate both auto-antibody-mediated and T-cell mediated immune pathologies. In the last few decades, extensive research in murine disease models has resulted in the elucidation of two novel anti-inflammatory mechanisms-of-action of IVIg: induction of FcγRIIB expression by sialylated Fc, and stimulation of regulatory T cells. Whereas controversial findings in mice studies have recently inspired intense scientific debate regarding the validity of the sialylated Fc-FcγRIIB model, the most fundamental question is whether these anti-inflammatory mechanisms of IVIg are operational in humans treated with IVIg. In this review, we examine the evidence for the involvement of these antiinflammatory mechanisms in the therapeutic effects of IVIg in humans. We demonstrate that although several elements of both immune-modulatory pathways of IVIg are activated in humans, incorrect extrapolations from mice to men have been made on the molecular and cellular components involved in these cascades that warrant for critical re-evaluation of these anti-inflammatory mechanisms of IVIg in humans

Dichotomal effect of space flight-associated microgravity on stress-activated protein kinases in innate immunity

Space flight strongly moderates human immunity but is in general well tolerated. Elucidation of the mechanisms by which zero gravity interacts with human immunity may provide clues for developing rational avenues to deal with exaggerated immune responses, e.g. as in autoimmune disease. Using two sounding rockets and one manned Soyuz launch, the influence of space flight on immunological signal transduction provoked by lipopolysaccharide (LPS) stimulation was investigated in freshly isolated peripheral blood monocytes and was compared to samples obtained from on-board centrifuge-loaded 1a'...g controls. The effect of microgravity on immunological signal transduction is highly specific, since LPS dependent Jun-N-terminal kinase activation is impaired in the 0a'...g condition, while the corresponding LPS dependent activation of p38 MAP kinase remains unaffected. Thus our results identify Jun-N-terminal kinase as a relevant target in immunity for microgravity and support using Jun-N-terminal kinase specific inhibitors for combating autoimmune disease

Patients treated with high-dose intravenous immunoglobulin show selective activation of regulatory T cells

Intravenous immunoglobulin (IVIg) is used to treat autoimmune and systemic inflammatory diseases caused by derailment of humoral and cellular immunity. In this study we investigated whether IVIg treatment can modulate regulatory T cells (Tregs) in humans in vivo. Blood was collected from IVIg-treated patients with immunodeficiency or autoimmune disease who were treated with low-dose (n=12) or high-dose (n=15) IVIg before, immediately after and at 7 days after treatment. Percentages and activation status of circulating CD4+CD25+forkhead box protein 3 (FoxP3+) Tregs and of conventional CD4+FoxP3- T-helper cells (Tconv) were measured. The suppressive capacity of Tregs purified from blood collected at the time-points indicated was determined in an ex-vivo assay. High-dose, but not low-dose, IVIg treatment enhanced the activation status of circulating Tregs, as shown by increased FoxP3 and human leucocyte antigen D-related (HLA-DR) expression, while numbers of circulating Tregs remained unchanged. The enhanced activation was sustained for at least 7 days after infusion, and the suppressive capacity of purified Tregs was increased from 41 to 70% at day 7 after IVIg treatment. The activation status of Tconv was not affected by IVIg. We conclude that high-dose IVIg treatment activates Tregs selectively and enhances their suppressive function in humans in vivo. This effect may be one of the mechanisms by which IVIg restores imbalanced immune homeostasis in patients with autoimmune and systemic inflammatory disorders