Original Article
Brief Report
Enhanced Humoral Immunity in Common Variable Immunodeficiency after Long-Term Treatment with Polyethylene Glycol-Conjugated Interleukin-2
N Engl J Med 1994; 331:918-921October 6, 1994
- Article
Common variable immunodeficiency is a primary immunodeficiency disease characterized by low serum concentrations of IgG, IgA, and usually IgM1,2. Although some patients appear to have only intrinsic B-cell defects, more than half also have abnormalities of T-cell activation and deficient secretion of interferon-γ and interleukin-2, -4, and -53-7. Most patients also have deficient production of a B-cell differentiation factor, a 34-kd protein that has been purified and lacks interleukin-2, -4, -6, and -10 activity8. We and others hypothesized that the B cells in this disease may be defective because of a lack of essential cytokines9-12. Because interleukin-2 can promote the secretion of immunoglobulin in vitro,13-16 in an earlier study we gave patients with hypogammaglobulinemia weekly intravenous doses of recombinant interleukin-2 conjugated with polyethylene glycol (PEG). After 12 weeks of treatment, in vitro immunoglobulin secretion by the patients' B cells had increased by a factor ranging from 10 to 10,00017. We then investigated the immunologic effects of subcutaneously administered PEG-conjugated interleukin-2. After 12 weeks, all patients had enhanced T-cell immunity, increased production of interleukin-2 and B-cell differentiation factor, and renewed production of serum antibody in variable amounts18. One of these patients, who showed clinical improvement, continued to receive PEG-conjugated interleukin-2 so that we could assess the long-term immunologic effects of this therapy. Because therapy greatly improved immunologic functions in vitro, immune globulin infusions were discontinued after 16 months of PEG-conjugated interleukin-2. Four months later, the patient's serum IgG concentration was still 4.2 times the base-line concentration, and there was evidence of renewed antibody production.
Case Report
Hypogammaglobulinemia was diagnosed in 1982 in a 50-year-old woman with a history of recurrent pneumonia, sinusitis, asthma, arthritis, giardiasis, diarrhea, diabetes mellitus, and viral cardiomyopathy. Her serum IgG concentration was 1.40 g per liter, serum IgA was 0.75 g per liter, and serum IgM was 0.35 g per liter. She had 79 percent T cells (26 percent helper and 35 percent suppressor) and 5 percent B cells. She was given a regimen of intravenous immune globulin infusions (400 mg per kilogram of body weight per month), but she still had recurrent sinopulmonary infections and two to three hospitalizations per year.
In March 1992, she began to receive weekly subcutaneous injections of PEG-conjugated interleukin-2 at a dose of 250,000 IU per square meter of body-surface area. Before the injections were begun she was given a booster dose of tetanus toxoid.
Methods
Protocol for PEG-Conjugated Interleukin-2
Recombinant interleukin-2 is covalently bonded to PEG 5000, which extends the half-life 10-fold with no loss of biologic activity19,20 (Cetus Oncology, Chiron, Emeryville, Calif.). To be eligible for treatment with PEG-conjugated interleukin-2 the patient had to have deficiency of two or more serum immunoglobulins, immunoglobulin secretion by helper T cells that was no more than 20 percent of normal, and an increase of at least 50 percent in in vitro T-cell proliferation in response to PEG-conjugated interleukin-217.
Lymphocyte Populations and Proliferation
Peripheral-blood mononuclear cells were isolated from blood samples taken before and at specific intervals after treatment with PEG-conjugated interleukin-217. The proliferative response of peripheral-blood lymphocytes to phytohemagglutinin, soluble antigens, tetanus toxoid, and Candida albicans was determined17. Populations of lymphocytes were analyzed with a fluorescence-activated cell sorter (FACS/IV, Becton Dickinson, Mountain View, Calif.) with monoclonal antibodies to CD3, CD5, CD8, CD4, CD20, and CD25 antigens (Becton Dickinson).
Assays for Interleukin-2, Interleukin-6, and B-Cell Differentiation Factor
For the interleukin-2 assay, mononuclear cells were stimulated for 6 and 24 hours with 1 μg of phytohemagglutinin per milliliter. For the interleukin-6 and B-cell differentiation factor assays, mononuclear cells were stimulated for 48 hours with 446, an anti-CD3 monoclonal antibody (1 μg per milliliter)21. The assays for interleukin-2 and interleukin-6 were bioassays22,23. The activity of B-cell differentiation factor was measured against the ability of B-cell differentiation factor from normal B cells to induce the secretion of immunoglobulin after exposure to Staphylococcus aureus17,21.
In Vitro Immunoglobulin Production
In vitro B-cell function was assessed by quantitating the amounts of immunoglobulin that B cells produced when stimulated in vitro by staphylococci alone or in combination with recombinant interleukin-2 or partially purified B-cell differentiation factor produced by normal T cells21.
Serum Immunoglobulins and Antibody Production
After 16 months of treatment with PEG-conjugated interleukin-2, intravenous immune globulin infusions were discontinued. After three months the patient was given a pneumococcal vaccine to assess antibody production. Antibodies to tetanus and diphtheria were measured three and four months after immune globulin infusions were stopped.
Results
Lymphocyte Proliferation
Within one month after the initiation of treatment with PEG-conjugated interleukin-2, the patient's mononuclear cells had increased proliferative responses to phytohemagglutinin. After five months the responses to tetanus toxoid and candida antigens increased markedly (Table 1Table 1
T-Cell Response to Treatment with PEG-Conjugated Interleukin-2.). There were no changes in the numbers of peripheral-blood B cells, natural killer cells, T-cell subgroups, or cells bearing interleukin-2 receptors.Production of Interleukin-2 and Interleukin-6
Before treatment with PEG-conjugated interleukin-2, the patient's mononuclear cells produced subnormal amounts of interleukin-2 after 6 and 24 hours of stimulation with phytohemagglutinin ( ≤ 2 U of interleukin-2 per milliliter, as compared with a mean [±SD] of 4.17 ±1.58 U per milliliter in similarly tested normal donor cells; range, 2.59 to 7.49). After 100 days of treatment, the patient's cells produced 15.5 U of interleukin-2 per milliliter. Her cellular secretion of interleukin-6, which was subnormal before therapy, increased 10-fold in response to treatment with PEG-conjugated interleukin-2 (from 3000 to 30,000 U per milliliter; mean [±SD] value in normal cells, 15,009 ±7551 U per milliliter; range, 3546 to 37,703).
B-Cell Differentiation Factor
Initially, the patient's mononuclear cells produced very little B-cell differentiation factor. However, this factor was detectable in stimulated T-cell cultures at six months, and the amounts continued to increase until they exceeded those in normal cells (Figure 1Figure 1
Effect of Treatment with PEG-Conjugated Interleukin-2 on the Production of B-Cell Differentiation Factor (Top Panel) and Immunoglobulin (Bottom Panel).). In contrast, the response of the patient's B cells to either S. aureus plus B-cell differentiation factor from normal T cells or S. aureus plus interleukin-2 increased rapidly after 30 days of PEG-conjugated interleukin-2, peaked after 110 days of therapy, and later fell to a level below that of normal donors (Figure 1).Serum Immunoglobulins and Antibody Production
Before treatment with PEG-conjugated interleukin-2, the patient's serum IgA concentration ranged from 0.75 to 1.05 g per liter (average, 0.80) and her serum IgM concentration ranged from 0.35 to 0.67 g per liter (average, 0.47). After 15 months of therapy, her IgA and IgM concentrations both increased, reaching a maximum at 15 months (IgA, 1.6 g per liter; IgM, 1.35 g per liter). Because of these increases and enhanced T-cell immunity, immune globulin infusions were stopped after 16 months of PEG-conjugated interleukin-2 therapy.
After the immune globulin infusions were stopped, there was a gradual decrease in serum IgG; after 60 days, the serum IgG stabilized between 5.1 and 6.0 g per liter. Even 123 days after the infusions were stopped, the patient's serum IgG concentration (5.9 g per liter) was still 4.2 times the initial concentration (1.4 g per liter) (Figure 2Figure 2
Serum IgG Concentrations before Treatment with Intravenous Immune Globulin and after Infusions Were Stopped.). Because the serum IgG concentration remained stable at a much higher level than was measured before immune globulin therapy was begun, renewed synthesis of immunoglobulin was suspected. Before the pneumococcal vaccination the patient had protective amounts of antibody to 6 of 12 pneumococcal serotypes; after vaccination she had increased amounts of antibody to 10 serotypes, resulting in protective titers to 10 of 12 serotypes (Table 2Table 2
Antibody Titers after Treatment with Intravenous Immune Globulin Was Stopped.)24. Similarly, antibody titers to both diphtheria and tetanus toxoids were stable three and four months after the immune globulin treatments were stopped (Table 2). Serum IgG subclasses, measured four months after immune globulin infusions were stopped, showed a deficiency of only IgG1.Clinical Effect
This study was designed to assess the immunologic effects of subcutaneously administered PEG-conjugated interleukin-2. However, treatment produced several clinical benefits, including cessation of chronic diarrhea and reduced respiratory tract infections, joint pain, and asthmatic symptoms. The patient had no serious infections and was not hospitalized during the study period. Adverse effects to PEG-conjugated interleukin-2 were mild and restricted to local skin reactions consisting of erythema and induration ranging from 4 to 9 cm in diameter.
Discussion
Intravenously administered PEG-conjugated interleukin-2 has a positive effect on the activity of helper T cells and boosts immunoglobulin and antibody production in vitro17. Since subcutaneous PEG-conjugated interleukin-2 can be safely administered by patients at home and has also been shown to be of benefit in cancer25 and infection with the human immunodeficiency virus (HIV),26 we have been investigating its immunologic effects in common variable immunodeficiency. Interleukin-2 promotes the growth and differentiation of CD4 (helper/inducer) T cells, CD8 (suppressor/cytotoxic) T cells, natural killer cells, and lymphokine-activated killer cells27-29. Other studies have shown that interleukin-2 can act directly and indirectly on activated B cells30-33.
In this study, prolonged subcutaneous administration of PEG-conjugated interleukin-2 produced markedly improved cellular immune functions, including increased T-cell proliferation in response to mitogens and antigens and restoration of lymphocyte secretion of interleukin-2, interleukin-6, and a novel B-cell differentiation factor. Because of these changes and the increased levels of serum IgA and IgM, immune globulin infusions were stopped to allow reassessment of B-cell function in vivo. Although the serum IgG concentration initially fell 50 percent, it subsequently stabilized at 4.2 times the pretreatment value, indicating renewed production of IgG. This was verified by our patient's response to pneumococcal vaccine and the stability of her protective antibody titers to tetanus toxoid and diphtheria. The half-lives of infused IgG1, IgG2, and IgG4 are between 18 and 23 days in normal subjects; IgG3 has a half-life of 7.5 to 9 days34. In subjects with hypogammaglobulinemia, the half-life of infused IgG may be prolonged,34 but the stabilization of serum IgG concentrations can only be explained by renewed production. Although we do not know what this patient's IgG subclass concentrations were before immune globulin treatment, her low initial IgG concentration (1.4 g per liter) suggests very low concentrations of most or probably all IgG subclasses. In contrast, after treatment with PEG-conjugated interleukin-2, she had only a moderate IgG1 deficiency.
The serum IgA and IgM concentrations increased dramatically 15 months after PEG-conjugated interleukin-2 was started and then declined. These increases coincided with enhanced production of B-cell differentiation factor. Although this factor continued to be secreted, the high concentrations of serum IgA and IgM were not sustained. We suspect that B-cell responsiveness in vivo may have changed during treatment, since the patient's B cells were originally responsive to B-cell differentiation factor, but not to S. aureus and interleukin-2. After PEG-conjugated interleukin-2, the responses to both stimulants increased dramatically but then declined.
Very few studies have used interleukin-2 in doses as small as the ones we used, even though a dose as low as 36,000 IU given twice weekly can substantially enhance cellular immunity26. Whether the effect of PEG-conjugated interleukin-2 in common variable immunodeficiency is primarily exerted on the T- or B-cell population is unclear. We conclude that although this disease has the phenotype of a humoral immunodeficiency disease, the lack of some still undefined T-cell factors may be the central immune defect. This hypothesis is consistent with previous observations that the modulation of T-cell activity in common variable immunodeficiency by cimetidine treatment35 or in HIV36 can improve or even restore humoral immunity.
Supported in part by grants from the National Cancer Institute (CA 53341), the National Institutes of Health (AI-23504 and AI 24671), the National Center for Research Resources (5 MO1-RR-0071, to the Mount Sinai General Clinical Research Center), and the Office of Orphan Products Development (FD-R-00358).
Source Information
From the Division of Clinical Immunology, Department of Medicine, Mount Sinai Medical Center, 1 Gustave Levy Pl., New York, NY 10029, where reprint requests should be addressed to Dr. Cunningham-Rundles.
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C. CUNNINGHAM-RUNDLES, K. KAZBAY, Z. ZHOU, L. MAYER. (1995) Immunologic Effects of Low-Dose Polyethylene Glycol-Conjugated Recombinant Human Interleukin-2 in Common Variable Immunodeficiency. Journal of Interferon & Cytokine Research 15:3, 269-276
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