|[Frontiers in Bioscience 1, e26-33, July 1, 1996]|
THERAPEUTIC APPLICATION OF INTRAVENOUS HUMAN NATURAL IMMUNOGLOBULIN
The Second Department of Surgery, Ehime University School of Medicine, Shigenobu, Ehime 791-02, Japan
Received 05/15/96; Accepted 06/12/96; On-line 07/01/96
The most reasonable application of HunIg is primary as well as secondary agammaglobulinemia (2, 19-21). Positive results have been observed in X-linked agammaglobulinemia with more than 400 mg/kg every three weeks (9). HunIg has been used in multiple myeloma, chronic lymphocytic leukemia and life threatening infections in patients with multiple myeloma (20-21). In these diseases, 150 to 300 mg/kg every three weeks for periods longer than 3 years have been used (19). Use of HunIg along with antibiotics has been associated with protection against recurrent bacterial infections in patients who suffer from IgG subclass deficiency such as IgG3 (2, 22). In addition, dramatic clinical improvements in symptoms such as those associated with hepatitis have been reported in these patients (23-24).
4.2. Idiopathic Thrombocytopenic Purpura (ITP)
HunIg has been successfully used in ITP with dramatic clinical effects (4, 25). The elevation of platelet number has been repeatedly observed (25). Applications for its use include episodes of severe bleeding, prophylaxis of intraoperative bleeding during major surgeries and delivery (10). The increase in platelet number may be the result of the blocking of the Fc-receptors of phagocytic cells such as monocytes/ macrophages and neutrophils (11). This hypothesis is supported by the finding that the F(ab')2 fraction of natural immunoglobulin preparation did not exert this effect at all whereas the Fc preparation did reveal this effect (10, 11, 12). The finding that the non-specific platelet activation in ITP patients was inhibited by anti-FcRII antibody also supports this hypothesis (26). Blocking the Fc-receptors impairs undesirable phagocytosis by Fc-receptor-expressing cells. It is quite likely that a relatively high concentration of natural immunoglobulin is necessary for the large increase in platelet number, since the blocking of Fc-receptors is generated by nonspecific binding to the Fc-receptor. In the related thrombocytopenias such as adult type ITP, heparin-associated thrombocytopenia (26), and Onyalai, a special form of immune thrombocytopenia in Africa (27), the immunoglobulin preparation also shows this effect. For septic thrombocytopenia, this preparation caused an elevation of platelet number and improvement of clinical symptoms via the anti-systemic inflammatory effect of the natural immunoglobulin (28).
4.3. Autoimmune Diseases
Autoimmune diseases is one of the most typical conditions for the use of human natural immunoglobulin preparation (29, 30, 31). The clinical improvement by HunIg may be related to blocking the Fc-receptors with the anti-cytokine activity of this preparation also playing a role (13). ITP is an autoimmune disease where anti-platelet autoantibodies play a critical role in platelet damage. However, the clinical effect of the immunoglobulin preparation in this condition is thought to depend exclusively on the Fc-blocking by the HunIg. There are several other autoimmune diseases where this preparation has been used. Among them, Kawasaki disease is a classic indication for the use of HunIg (32, 33). Kawasaki disease is believed to be a viral infection where autoimmune processes contribute to its symptomatology. HunIg should be effective in the systemic inflammation that is seen in Kawasaki disease. Prevention of coronary lesions has been observed when this preparation has been used during the acute phase of the disease (34). Although several modes of usage exist for the treatment of this disease, administration of a single large dose (1 to 2 g/kg) of HunIg along with antipyretics is typically recommended (34, 32). This method of administration of the HunIg is also most cost effective.
Use of HunIg has also been used in Guillain-Barre syndrome (35, 36, 37). The pathophysiology of this disease is an acute demyelinating polyneuropathy caused by an autoimmune process. Along with the use of steroid hormone, administration of 400 mg/kg/day of natural immunoglobulin preparation for several days has been recommended (35). Plasma exchange therapy is another mode of therapy with HunIg (36).
Systemic vasculitis of autoimmune origin is another indication for the clinical use of HunIg preparation (38, 39). With the use of HunIg, patients with vasculitis with positive anti-neutrophil cytoplasmic antibody show improvement in their clinical symptoms (40).
HunIg has also been used in other autoimmune diseases such as myositis and myopathies (41). Granulomatous disorders such as Wegener's granulomatosis, lupus erythematosus-related symptoms and juvenile arthritis, autoimmune-mediated chronic active hepatitis, chronic glomerulonephritis with autoimmune etiology, Graves' ophthalmopathy and pretibial myxedema, multiple sclerosis and neurologic autoimmune diseases have also been targets for the treatment with HunIg (42-44). There are many reports of other autoimmune diseases treated by this preparation; however, the clinical effectiveness of HunIg against these disorders has not been clearly established.
Allergic disorders including asthma is one indication for the use of human immunoglobulin preparation (45, 46). The mechanism of action of HunIg in these disorders is most likely related to both the Fc-blocking and anti-cytokine attributes of HunIg. Improvements of symptoms and reduction in the dosage of steroid hormones have been reported during and after 4 months of intravenous immunoglobulin therapy (47). However, the effect of HunIg appears to be variable from patient to patient, and its repeated use requires careful monitoring of the symptoms of the patients.
4.5. Systemic Inflammation Associated Disorders
Systemic inflammation in neonates, especially those in the high-risk group is an indication for the use of HunIg (48, 49, 50). When used in the early phase of bacterial infections in conjunction with antibiotics, natural immunoglobulin preparation reduced the mortality rate of neonates (48). Along with the use neutrophil transfusion, HunIg has also been used as a supplemental therapy (22). The possible mechanisms of action of HunIg are the anti-cytokine activity of HuIg along with inactivation of complements. Improvements of immunologic and hematologic parameters were reported when HunIg was included in the treatment of premature infants with group B streptococcal infections (49, 51). In such patients, administration of 500 to 750 mg/kg is generally recommended (49, 50). Children with acute intestinal infections, neonatal neutropenia, neonatal bacterial sepsis or refractory infections are distinct clinical conditions for the use of HunIg (53, 54, 55). 200 to 500 mg/kg of HunIg may be most effective when used for prevention of infection in preterm infants who are at high risk for developing infection (52). The prophylactic use of HunIg in the late phase of infection in low-birth weight neonates has also been strongly recommended (48). However, no clear benefits were reported when HunIg was used in these conditions (50). Randomized studies should be carefully carried out in the use of HunIg in these disorders, and clear guidelines for of this preparation should be established (56).
Although HunIg has been extensively used in shock, sepsis and multiple organ failures, some have failed to observe to demonstrate a significant improvements upon its use in these conditions (1, 28, 57, 57, 58). Administration of HunIg has also been advocated for severe infections in the field of surgery (59) as well as in trauma and burned patients (60, 61).
HunIg has been used in spastic disorders (62, 63, 64) such as West (62, 64), and Lennox-Gestaut (62) syndromes. However, particularly in these syndromes, the clinical improvements have been disappointing (62, 64). The use of HunIg has been suggested as an alternative treatment strategy when other treatments such as ACTH have failed (64). HunIg has also been used in the treatment of epilepsy that has an immunogenetic basis (64).
Patients with multifocal motor neuropathy and polyneuropathy associated with monoclonal gammopathy (65, 66) as well as patients with chronic demyelinating neuropathy (67) were reported to exhibit clinical improvement by the use of HunIg.
4.8. Renal Failure
The therapeutic effect of HunIg in acute renal failure has been controversial (68, 69). While a significant reduction in mortality rate has been observed when HunIg has been administered to these patients (68), no beneficial effect was reported for major complications of the disorder (68). The therapeutic effectiveness of HunIg has been shown in acute renal failure associated with rhesus hemolysis (70). Given that this disorder is immune-complex mediated, it is not hard to realize why HunIg has been found useful in this condition.
4.9. Other Diseases
HunIg has been used for the treatment of many other diseases. These conditions include chronic lymphocytic leukemia, multiple myeloma, lymphoma, chronic fatigue syndrome, recurrent acute otitis media, chronic relapsing colitis, (20, 21, 56, 71), and AIDS (56, 72, 73). The effectiveness of combination of HunIg-zidovuzine has been tested in the treatment of AIDS (72). However, the effect by this combination treatment was not prominent.