Intravenous immunoglobulin and cytokines: focus on tumor necrosis factor family members BAFF and APRIL.

The presence of natural autoantibodies against cytokines has been reported in healthy individuals. Because circulating cytokines may be implicated in the clinical outcome of numerous diseases, the mode of action of intravenous immunoglobulin (IVIg) (pooled from sera over a thousand normal individuals) may involve immunomodulation of the cytokine network. We review the anti-cytokine effects of IVIg as well as the consequences of IVIg infusions on cytokine production. Furthermore, IVIg exerts therapeutic effects in autoimmune diseases and lymphoid malignancies. These two conditions have in common an overproduction of BAFF (for B-cell-activating factor of the TNF family). The presence of antibodies with BAFF and APRIL (a proliferation-inducing ligand) specificity was investigated. We found that IVIg recognizes BAFF and APRIL and that IVIg binding prevents BAFF from exerting its antiapoptotic effect on B cells. These anti-BAFF IgGs might prevent the deleterious effects of BAFF in B-cell-mediated autoimmune diseases.

Autoantibodies in nonautoimmune individuals during infections.

Infections can act as environmental triggers inducing or promoting autoimmune disease in genetically predisposed individuals. Identification of microbial peptides similar to self-tissues may by molecular mimicry, provide the inducing mechanism for an immune response. The aim of this study was to identify autoantibodies (autoAbs) in nonautoimmune individuals during acute bacterial, viral, or parasitic infections. Specific Abs or specific infections with an increased autoAb load may shed insight into the mechanisms of autoimmune disease. Sera from 88 patients with acute infections (41 bacterial, 23 viral, 17 parasitic, and 7 rickettsial) were tested by the ELISA method for antinuclear antibodies (ANA) 8 Pro, and Abs to thyroid peroxidase (TPO), thyroglobulin, phospholipids, annexin-V, laminin, anti-Saccharomyces cervisiae (ASCA), and prothrombin, along with 80 normal controls. Elevated titers of Abs to annexin-V and prothrombin were the most prevalent in viral, parasitic, and rickettsial infections and to laminin in viral and parasitic infections. Elevated titers of ASCA and ANA were found in viral and bacterial infections. Antiphospholipid Abs were found in parasitic and Q-fever infections. Thirty-four individuals harbored elevated titers of at least two Abs. An autoAb burden was detected in individuals with hepatitis A, hepatitis B, toxoplasma or Q-fever infections. In nonautoimmune individuals with various (bacterial, viral, parasitic, and rickettsial) infections, elevated titers of Abs to annexin-V, prothrombin, laminin, ASCA, ANA, and phospholipids were most frequently detected.

Immunomodulatory effects of intravenous immunoglobulins as a treatment for autoimmune diseases, cancer, and recurrent pregnancy loss.

Intravenous immunoglobulin (IVIG) is a safe preparation, made of human plasma of thousands of healthy donors. The fascinating history of gamma globulin therapy begins in 1930 when Finland treated pneumococcal pneumonia patients with equine serum, which prolonged their survival from pneumonia. Since then, significant breakthroughs were achieved by Cohn, Bruton, Imbach, and others, whose clinical contribution to the world of medicine was of great importance. Originally IVIG was used to treat immunodeficiencies. Later on the use of IVIG extended to autoimmune diseases as well. The efficacy of IVIG has been established only in several autoimmune diseases; clinical reports of trials, series, and case reports indicate significant improvement in many more autoimmune diseases. IVIG have also showed antimetastatic effects in a variety of cancer cell lines, as well as in a few case reports. The efficiency of IVIG has also been observed in recurrent pregnancy loss (RPL), either as a result of an autoimmune disease or spontaneous. Several attempts were made to discover the immunomodulatory effects of IVIG, but it is still not fully understood. Clearly IVIG has multiple mechanisms of actions, which are thought to cooperate synergistically. One of the main mechanisms of actions of IVIG is its ability to neutralize pathogenic autoantibodies via anti-idiotypic antibodies within IVIG preparation. The ability of IVIG to neutralize pathogenic autoantibodies is of great importance in many autoimmune diseases, as well as in RPL. In cancer cell lines, IVIG modulates the immune system in a few ways, including the induction of IL-12 secretion, which consequently activates natural killer cells, and the induction of expression of proapoptotic genes only in cancer cells. Side effects from IVIG are rare and mostly mild and transient. More importantly adverse effects can be minimized by administration to a selective patient population in a proper way: slow infusion rate of 0.4 g/Kg body weight IVIG for 5 consecutive days, given in monthly cycles. The only downside of IVIG therapy is its high price. Therefore, clinicians should balance efficiency versus cost in deciding whether or not to treat certain conditions with IVIG.

Facing the enigma of immunomodulatory effects of intravenous immunoglobulin.

Intravenous immunoglobulin (IVIg) is a safe remedy for a number of conditions; it is produced from human plasma of thousands of healthy donors. The therapeutic effect of IVIg lies within its content. IVIg contains natural antibodies, which are more polyreactive than immune antibodies, including immunoglobulin G antibodies against endogenous and exogenous antibodies, immunomodulating peptides, and varies cytokines. Beneficial effects of IVIg have been established in immunodeficiencies, as well as in some autoimmune diseases. Also, numerous therapeutic effects of IVIg have been reported over the years in varies autoimmune diseases, recurrent pregnancy loss, and cancer. Many proposed immunoregulatory mechanisms of action of IVIg have been suggested. Some of them have been proven, others are still an enigma, at least in part. Some of these mechanisms entail (a) Fc-receptor blockade; (b) neutralization of pathogenic autoantibodies via idiotypic and anti-idiotypic antibodies; (c) effects on the Fas apoptotic pathway via agonistic and antagonistic anti-Fas autoantibodies; (d) regulation of complement components; (e) modulation of cytokine secretion; (f) hindrance of natural-killer cell activity; (g) inhibition of matrix metalloproteinase-9; (h) suppression of NFkB activation and IkB degradation; (i) G1 cell cycle arrest; (j) prevention of tumor growth; (k) decrease in leukocyte recruitment; (l) attenuation of T-cell stimulation; (m) effects on antibody kinetics; and (n) effects on dendritic cells. The variant mechanisms of IVIg are believed to cooperate in a synergistic way, which all together point to IVIg as a therapeutic preparation with anti-inflammatory, antiself-reactivity, antimetastatic, and embryo-protective effects. This article reviews several main mechanisms of IVIg in order to shed some light on the set of therapeutic effects of IVIg, which are not yet fully understood.

Uncovering the hidden potential of intravenous immunoglobulin as an anticancer therapy.

Intravenous immunoglobulin (IVIg) is a safe preparation made from human plasma. The original concept of IVIg as an anticancer drug was built up over the years, after numeral reports were accumulated indicating cancer regressions after IVIg administration. Because IVIg is basically an established remedy for immunodeficiencies and several autoimmune diseases, the association between beneficial effects in cancer patients after IVIg was first seen in patients who had both cancer and autoimmune or immunodeficiency diseases. Interestingly, cancer and autoimmunity share several common features, which together enhance the notion of using IVIg to treat cancer. Several studies tested the broad range of the antimetastatic effects of IVIg. IVIg was found to operate in many different and complex ways, among them (a) induction of interleukin-12 secretion, leading to natural-killer-cell activation; (b) inhibition of matrix metalloproteinase-9 mRNA expression; (c) suppression of tumor cell growth; (d) hindrance of nuclear factor kappaB activation and IkappaB degradation; and (e) G1 cell-cycle arrest. In conclusion, IVIg is a potential anticancer treatment for several reasons: (a) the bidirectional relationship between cancer and autoimmunity; (b) the apparent association between cancer regression and IVIg administration; (c) a variety of anticancer effects of IVIg observed; and (d) IVIg is considered to be a safe preparation with minimal side effects. Obviously, prospective controlled studies that will establish the antitumor effects of IVIg are needed.

Intravenous immunoglobulin and recurrent pregnancy loss.

Intravenous immunoglobulin (IVIg) has been used to prevent pregnancy loss, in unexplained recurrent miscarriage, and in antiphospholipid syndrome (APS). When used on an unselected population with recurrent miscarriage, IVIg has not been shown to improve the live birth rate. However, when patients are selected for poor prognosis or autoimmune phenomena, IVIg has been shown to be effective. This article discusses the possible immune mechanisms by which IVIg may act and the effect of confounding factors such as embryonic chromosomal aberrations or anti-beta2-glycoprotein I antibodies in APS. Hence, there may be an impression of futility, when IVIg may be highly effective in saving those pregnancies that can be saved. Additionally, in an unselected population with recurrent miscarriage, there is a relatively good prognosis for a subsequent live birth (60%). Therefore, the spontaneous prognosis must be taken into account, which has not been the case in previous trials.

[Intravenous immunoglobulin (IVIG) as treatment for recurrent pregnancy loss (RPL)].

Miscarriages are the most common complication in human pregnancies. Recurrent pregnancy loss (RPL) could occur for several reasons, such as: immunological abnormalities of the pregnant women and chromosomal abnormalities of the embryo. There are several autoimmune characteristics for RPL, such as autoantibodies, and sometimes RPL are a symptom of an autoimmune disease. It is unclear whether the autoantibodies are the cause, the consequence or an artifact of the RPL. Intravenous immunoglobulin (IVIG) is a preparation made of purified plasma of thousands of healthy donors. Currently, IVIG is provided as a treatment for several autoimmune diseases. There are reports on a beneficial effect of IVIG for women with RPL of unknown reason. Some reports indicate a beneficial effect of IVIG independent of aspirin, as well as in artificial fertilization. Nevertheless, the efficacy of IVIG has yet to be established. Perhaps a certain sub-group should be defined of women who suffer from RPL and have greater odds for successful IVIG treatment. A sub-group analysis showed that, in secondary RPL, IVIG is more successful when provided after embryo implantation, whereas, in primary RPL, IVIG is better when provided prior to conceiving. Apart from the miscarriage type (secondary or primary) other factors that might influence the IVIG-treatment success were found: the number of previous miscarriages, the age of the pregnant women and the way IVIG is administrated. The mechanisms of action of IVIG in RPL are multiple, complex and not fully understood. IVIG therapy regulates the immune system in several mechanisms, in a way that might increase the survival rate of the embryo in the uterus and might decrease the odds of a miscarriage. For example, one of the main mechanisms of IVIG in RPL is down-regulation of natural killer cells (NK cells) activity and expression. This finding is of great importance because it has been reported that women who have never given birth and have high levels of NK cells in their peripheral blood have higher chances of pregnancy loss. In conclusion, IVIG is an immunomodulator that exerts its beneficial effects in multiple mechanistic ways acting together synergistically. IVIG is a potential treatment for women with RPL as a result of immunological abnormalities.