Intravenous immune globulins. A review of their uses in selected immunodeficiency and autoimmune diseases.

Intravenous immune globulin (IGIV) was introduced a decade ago as a therapy for primary immunodeficiency diseases. It proved to be a valuable therapeutic substance for this purpose and is now considered to be the treatment of choice. The intent was to supply ubiquitous anti-infectious agent antibodies through passive immunisation to replace deficient circulating antibody content. During such therapy, unexpected benefits were noted in thrombocytopenic patients. Since that time, the therapeutic indications for IGIV infusions have greatly increased, with a particular interest in infectious, haematological and autoimmune diseases. This review summarises the status of IGIV therapy in haematological diseases within the categories of primary immunodeficiency diseases, secondary immunodeficiency states and autoimmune syndromes. The majority of firm data have been gathered on the treatment of patients with primary immunodeficiency disease. These data are reviewed from the aspect of anticipated therapeutic response and side effects. Emphasis should be placed on the IgG circulating blood levels as there is a need for individualizing therapy because of marked interindividual patient variation. The use of IGIV therapy in primary and secondary immunodeficiency states should consider the potential benefits to be attained in haematological malignancies and related complications which may be magnified by chemotherapy and radiation therapy. The mode of action of IGIV in autoimmune diseases, although not yet precisely determined, may involve establishing reticuloendothelial blockade or immunomodulation by supplying anti-idiotype antibodies.

Home-based immunoglobulin infusion therapy: quality of life and patient health perceptions.

Thirty-seven antibody-deficient patients who were participating in a multicenter trial evaluating home-based, self-administered IVIG therapy anonymously completed questionnaires regarding beliefs concerning health control, quality of life, and attitudes toward active participation in medical care. Their responses were compared with a group of 29 patients undergoing traditional IVIG therapy in a medical clinic setting. A subsample of the home-based group who later returned to clinic-based IVIG therapy allowed comparison of responses given by the same patients in both settings. Home-based therapy was preferred to clinic-based therapy. Independence, convenience, comfort, decreased disruption of activities, travel time, and costs were specific factors rated most favorably. On the Health Belief Questionnaires, patients preferred informed, self-involved medical care regardless of the setting for their IVIG treatments.

Prospective study on the hepatitis safety of intravenous immunoglobulin, pH 4.25.

Recent reports of transmission by intravenous gamma-globulin preparations of non-A non-B hepatitis (NANBH), including several cases that progressed to severe liver damage and death, have raised concerns about the safety of intravenous gamma-globulin. However, the problem does not seem to be widespread. To assess this issue, we previously reported the results of liver function tests monitored in 41 patients with primary immunodeficiency treated with intravenous immunoglobulin (IGIV), pH 4.25 over periods ranging from 6 to 15 months. Eighteen of these patients at two of the three centers have now had serial serum glutamic pyruvic transaminase (SGPT) levels performed regularly at intervals of 1-5 weeks while continuing monthly intravenous infusions of nonmodified IGIV, pH 4.25 for an additional 14-26 months. The standard dosage was 400 mg per kg body weight IGIV, pH 4.25. Six lots of IGIV, pH 4.25 were used. Transient minor SGPT elevations were observed in 5 of the patients on a total of 8 occasions. None of the elevations was considered indicative of NANBH or of any chronic hepatic disease. All patients remained negative for hepatitis B surface antigen throughout the study.

Non-A non-B hepatitis and the safety of intravenous immune globulin, pH 4.2: a retrospective survey. Preliminary communication.

Evidence for transmission of non-A non-B hepatitis (NANB) was sought in 41 patients with primary immune deficiency who were receiving human intravenous immune globulin (IGIV) over periods ranging from 6 to 15 months at a monthly dosage of 400 mg/kg body weight. One lot of a reduced and alkylated IGIV and three lots of a nonmodified preparation stabilized at pH 4.2 were used. No evidence of NANB was found, although transient elevations in serum glutamic pyruvic transaminase (alanine aminotransferase) were found in 6 of the patients. The possible causes of the elevated levels in these 6 patients are discussed.

Clinical use of a new pH 4.25 intravenous immunoglobulin preparation (gamimune-N).

A multicentre, randomised, double-blinded, cross-over study was done to evaluate the clinical use and safety of a new immunoglobulin preparation for intravenous use (IVIgG). This reagent, IVIgG pH 4.25, was compared to a standard commercially available preparation IVIgG pH 6.8. Thirty-nine patients with primary immunodeficiency disease received a total of 232 infusions at a dose of 400 mg/kg every 4 weeks. Adverse effects from such infusions were transient and minimal. Clinically significant abnormalities did not occur. There were no statistically significant differences between the results for IVIgG pH 6.8 and for the new IVIgG pH 4.25 preparation. It was possible to infuse the new IVIgG pH 4.25 reagent at rates of 0.1 ml (5.0 mg)/kg/min without inducing vasomotor adverse effects.

Safety and toxicity of a new serum immunoglobulin G intravenous preparation, IGIV pH 4.25.

A new preparation of serum immunoglobulin G for intravenous use (IGIV) was investigated. The reagent, IGIV pH 4.25, is a liquid preparation of native, unmodified human serum IgG without preservatives but stabilized in 10% maltose. Its physical characteristics have multiple advantages over those of other available IGIV preparations. In a multicenter, randomized, double-blind, crossover study, this product was compared with a commercially available standard preparation, IGIV pH 6.8. Thirty-nine patients with various forms of primary immunodeficiency disease received infusions consisting of 400 mg/kg every four weeks; an overall total of 232 infusions were administered. Extensive clinical and laboratory observations were made. Adverse effects from infusion therapy were transient and minimal. No clinically significant abnormalities in vital signs and laboratory values occurred. There were no statistically significant differences between the results for IGIV pH 6.8 and those for the new IGIV pH 4.25 preparation. It was possible to infuse the new IGIV pH 4.25 reagent rapidly (0.1 ml/kg per hr) without inducing vasomotor adverse effects.

Intravenous immune globulin therapy in hypogammaglobulinemia. A review.

An immune globulin preparation specifically modified for intravenous administration has been employed therapeutically in 30 patients with primary immunodeficiency disease. Our results of this long-term study are summarized within three major categories: (1) Levels of serum IgG produced and maintained after intravenously administered serum immune globulin infusions of 100 to 500 mg/kilo. The disappearance pattern of infused IgG is outlined and individual patient variations emphasized. (2) The therapeutic effects of intravenously administered serum immune globulin therapy are reported and related to dosages of intravenously administered serum immune globulin administered and serum levels of IgG maintained. (3) The incidence and nature of detrimental side effects are outlined, and methods to reduce this problem are indicated. It is recommended that patients with primary immunodeficiency be given from 150 to 200 mg/kilo intravenously administered serum immune globulin, every four weeks, as prophylactic therapy to reduce acute infectious complications. A method to establish an optimum therapy for a specific patient is presented.

Prolonged interval high-dose intravenous immunoglobulin in patients with primary immunodeficiency states.

Intravenous immunoglobulin can be a very effective form of treatment for patients with primary immunodeficiency states. Recommendations for intravenous dosing previously have been empirically derived. In order to determine the potential prolongation of intervals between infusions following the administration of 500 mg/kg of intravenous immunoglobulin, 11 patients were studied. This high-dose therapy was well tolerated and resulted in a modest prolongation of therapeutic IgG levels when compared with lower-dose 150 mg/kg regimens. Significant variability among individual patients was observed. Implications of this high-dose therapy are discussed.

Noncytotoxic inhibition of malignant cell growth by Ulex seed extracts.

A water-soluble, boiled extract produced from the seeds of Ulex europeus (European gorse) was found to inhibit the growth of various reticuloendothelial tumor cell lines. Seven tumor cells, six murine and one human, were investigated and found to be sensitive to the inhibitory activity of such extracts. Ulex seed extracts (USE) reduced the incorporation of tritiated thymidine by tumor cells in an exponential dose - response relationship. In addition, 5- to 8-day cultures of these cell lines grown in the presence of USE had a marked reduction of tumor cell numbers. The reduction in growth exhibited a dose - response relationship. Growth inhibition was not the result of cytotoxicity. Cell viability and washout studies demonstrated the impermanence and easy reversibility of the inhibiting state.

Diet-induced systemic lupus erythematosus (SLE) in primates.

Ten adult, female cynomolgus macaques were randomly assigned to two equal groups: (1) semipurified diet (SPD); and (2) SPD with 45% ground alfalfa seed (AS). Both groups were studied at monthly intervals after 5 mo on their respective diets. Control animals had a mean hematocrit (Hct) of 43 +/- 2%, negative antiglobulin (AG), antinuclear antibody (ANA) and LE cell tests. Mean values for C3 and C4 were 309 +/- 47 mg/dl and 35 +/- 7 mg/dl, respectively. Mean serum binding to radiolabeled double stranded deoxyribonucleic acid (dsDNA) was 1.9 +/- 0.2%. Three of five animals fed AS developed signs of an SLE-like illness characterized by AG-positive anemia (lowest Hct 30%), positive ANA (highest titer greater than 1:15, 360; rim pattern) and elevated anti-dsDNA binding (highest 96%) with variable degrees of hypocomplementemia. One animal had granular deposition of immunoglobulin and complement at the dermal-epidermal junction of clinically normal skin the presence of immune complex-induced glomerulonephritis.

Individual patient variations in the kinetics of intravenous immune globulin administration.

Subjects with primary immunodeficiency received modified immune serum globulin (IGIV) intravenously at various dose levels in long-term therapeutic studies. Therapy was effective and essentially free from adverse reactions. Two pertinent observations were made relating to the attained levels of serum IGG. Over a dose range of 100-225 mg/kg, the serum IgG level directly reflects the dosage administered. Sequential analysis of serum levels of IgG demonstrated three patient populations in 14 subjects receiving 150 mg/kg. The largest group, nine patients, had progressive reduction of serum IgG values compatible with the half-life of the reagent, with a return to the original serum IgG level in four weeks. A second population of four patients had a slower reduction of serum IgG over the four-week period. IgG values were significantly elevated over baseline values at the time of the next due infusion. In one subject serum IgG values varied greatly with rapid drops and elevations unrelated to the infusion.

Systemic lupus erythematosus-like syndrome in monkeys fed alfalfa sprouts: role of a nonprotein amino acid.

Hematologic and serologic abnormalities similar to those observed in human systemic lupus erythematosus (SLE) developed in cynomolgus macaques fed alfalfa sprouts. L-Canavanine sulfate, a constituent of alfalfa sprouts, was incorporated into the diet and reactivated the syndrome in monkeys in which an SLE-like syndrome had previously been induced by the ingestion of alfalfa seeds or sprouts.

Ulex seed extracts: lymphocyte growth inhibition and the anti-H hemagglutinins.

Extracts produced from the seeds of Ulex europaeus are commonly used for their ability to react with the H basic substance present on erythrocytes and secreted in body fluids. Such extracts were found to also contain a potent inhibitor of human and murine lymphocyte growth. Inhibition of growth does not result from cytotoxicity and is easily reversible. Ulex seed extract (USE) solutions were modified in various ways to produce reagents in which the anti-H hemagglutinins were either retained or removed. The fractionated solutions were then analyzed for hemagglutination and lymphocyte growth-inhibiting activity. Such studies clearly indicated that these two biological functions resulted from the action of different materials. The lymphocyte growth inhibitor is not a glycoprotein lectin. It does not mediate its effect through the H basic substance and is a heat-stable, small molecule. The data suggest that plant seed extracts employed for their lectin content may contain an additional class of biologically active agents potentially useful in man.

Inhibition of lymphocyte growth by Ulex seed extracts (USE).

Extracts produced from the seeds of Ulex europeus (European gorse) were found to contain an inhibitor of human and murine lymphocyte growth. Interference with lymphocyte growth was demonstrated in three test systems. (1) Ulex seed extracts (USE) prevented the uptake of tritiated thymidine by stimulated human T and B lymphocytes. (2) The numbers of sensitized murine lymphocytes releasing antibody were diminished after incubation with USE. (3) Murine lymphoid tumour cells cultured in the presence of USE had a reduced growth potential. Growth inhibition occurred independently of the mode of lymphocyte stimulation. Increased metabolic activity induced by plant seed mitogens, alloantigens and direct immunization, as well as that endogenously present in rapidly growing tumour cells, was similarly restricted. The inhibition of lymphocyte growth was not the result of cytotoxicity and was easily reversible by washing lymphocytes free of USE. The USE growth inhibitor was found not to be anti-H and appeared to function as an antithesis of stimulators found in other plant seed extracts.

The effect of anti-thymocyte antiserum in progressive myasthenia gravis.

The therapeutic effect of goat anti-human thymocyte antiserum globulin (ATG) was assessed in ten patients with myasthenia gravis. Five patients had undergone prior thymectomy. All subjects had far-advanced, debilitating and progressing disease poorly responsive to classic anticholinesterase therapy. Prolonged, low dose ATG therapy was used with 1.0-2.6 grams/protein administered intramuscularly over a 28-73 period. Depression of cellular immunity was observed with anti-thymocyte antiserum was more profound in patients with a prior thymectomy. Therapeutic responses of varying degrees were noted in 8 out of 10 patients. Completion of a course of ATG and discontinuation of the drug did not lead to acute relapse states. Follow-up examinations for over five years have been maintained. A mean remission period of approximately two years was observed. It is suggested that this therapy deserves further evaluation. Subjects with prior thymectomy and progressive disease may represent the most ideal candidates.

Safety and patient acceptability of intravenous immune globulin in 10% maltose.

The safety and patient acceptance of two preparations of modified (reduced and alkylated) immune globulin for intravenous use were evaluated; one preparation was formulated as a 5% solution in 10% maltose (IGIV-maltose), the other did not contain maltose (IGIV). In this double-blind trial each of 29 immunodeficient patients received three consecutive monthly infusions (100 or 150 mg/kg immune globulin) of one preparation before being crossed over to the other. Only 3 of 29 patients had adverse reactions when on IGIV-maltose, compared with 22 who had side-effects during infusions of IGIV (p < 0.001). Adverse reactions were recorded during 3 of 87 IGIV-maltose infusions and during 51 infusions with the maltose-free IGIV (p < 0.001). 27 patients expressed preference for IGIV-maltose. IGIV-maltose seems safe and will permit rapid infusion of large doses of immune globulin, thus improving the management of patients with antibody deficiency diseases.

Lack of oncogenicity with immunosuppressive therapy.

The effect of immunosuppressive therapy on the incidence of malignancy was examined in BALB/c mice. In a short (31-week) protocol study, malignancy was induced by inoculating animals with 10(2.1) ID50 of lymphatic leukemia virus. Antilymphocyte antiserum and azathioprine increased the mortality and shortened the latency period of leukemia. Combining these two agents had a synergistic effect. The concept of immunological surveillance was investigated in a long-term protocol using the identical animal and immunosuppressive systems. Mice did not receive leukemia virus and were observed for development of spontaneous malignancy. Significant immunodepression was demonstrated after 348 days of immunosuppressive therapy. After two years, all surviving animals were killed and examined for neoplasia. There was no evidence that immunodepression increased the incidence of spontaneous malignancy. Immunosuppression adversely influenced exogenously administered, virus-induced murine leukemia. However, immunosuppressive therapy was not innately oncogenic and the concept of immunological surveillance was not confirmed.

Intravenous immunoglobulin therapy for antibody deficiency.

Twenty patients with antibody deficiency were treated at random with either intramuscular immune serum globulin (ISG) or intravenous modified immune serum globulin (M-ISG). Fourteen patients received of 259 M-ISG infusions during 242 months of treatment. Catastrophic vasomotor reactions were not observed. A single dose of 150 mg/kilo M-ISG increased serum IgG values a mean 248 mg%. Intravenous M-ISG therapy was effective in reducing the incidence of acute infections. Subjects receiving M-ISG developed 0.103 acute infections per month of treatment. Patients injected with ISG had 0.295 acute infections per month of treatment. Seven subjects had separate courses of both intravenous M-ISG and intramuscular ISG. Acute infections per month of treatment for M-ISG and ISG were 0.104 and 0.406, respectively.

Myasthenia gravis treated with purified antithymocyte antiserum.

The therapeutic effect of goat anti-human thymocyte antiserum globulin (ATG) was assessed in 10 patients with myasthenia gravis. All subjects had far-advanced, debilitating disease poorly responsive to anticholinesterase therapy. Prolonged, low-dose ATG therapy was used, with 1.0 to 2.6 gm ATG protein administered intramuscularly over a 28- to 73-day period. Therapeutic responses of varying degrees were noted in 8 of 10 patients. Completion of a course of ATG treatment and discontinuation of the drug did not lead to acute relapse. Follow-up examinations for over 5 years have been maintained. A mean remission period of approximately 2 years was observed. This therapy deserves further evaluation; subjects with progressive myasthenia gravis despite prior thymectomy may represent ideal candidates.

Immunologic aspects of malignancy.

Animal experimental studies and clinical observations closely relate the development and course of malignancy with immune function. The immune apparatus serves as a homeostatic system capable of recognizing "sell" from "non-self." Neoplasia is characterized by new surface components against which immune reactivity may be directed. Subpopulations of lymphocytes are stimulated by such tumor antigens leading to both humoral and cellular responses. Immunodeficiency, the surveillance role of immune responses, and immune competition are intimately concerned with the eventual outcome of the malignant state. These concepts are examined as supplying the theoretical background for development of new therapeutic procedures. Immunotherapy in the future may offer the most effective means of controlling the neoplastic state.