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.

Immunoglobulins on the surface of lymphocytes. IV. Distribution in hypogammaglobulinemia, cellular immune deficiency, and chronic lymphatic leukemia.

The distribution of peripheral blood lymphocytes that contain surface Ig has been studied by means of immunofluorescence in humans. Normal individuals, individuals with sex-linked and acquired agammaglobulinemia, selective IgA deficiency, cellular immune deficiencies, and individuals with chronic lymphatic leukemia (CLL) were studied. Approximately 28% of the peripheral blood lymphocytes from normal individuals contained surface Ig. On an average 15% contained IgG, 6%, IgA, and 8%, IgM; and the kappa: lambda ratio was 2:1. Lymphocytes from patients with CLL appeared to be "monoclonal" in that the cells from a given individual had a single Ig associated with them (e.g., kappa IgM). In three-quarters of the cases the H chain class was IgM; in the remaining one-quarter no H chain could be detected on the cell surface. The L chain class was kappa in 12 cases and lambda in 8. Four patients with sex-linked agammaglobulinemia and one with "acquired" agammaglobulinemia had markedly decreased numbers of cells with surface Ig (0-4%). In contrast, the three patients with selective IgA deficiency and no detectable serum IgA contained normal numbers of cells (6-8%) with surface IgA. Five patients with cellular deficiency states, including two with Wiskott-Aldrich syndrome, contained a normal or low percentage of cells with surface Ig.

Antigen heterogeneity of human B and T lymphocytes.

Rhesus monkeys were immunized with normal human lymphoid cells, cultured lymphoid cells, and chronic leukemic lymphocytes. Antisera were analyzed by cytotoxicity and immunofluorescence techniques to study the antigenic characteristics of human lymphocytes. In an attempt to obtain a reagent specifically reactive with T (thymus-derived) lymphocytes, an antispleen antiserum was absorbed with cellf from five B- (bone marrow-derived) cell lines. After absorption, the antiserum killed 60-75% of peripheral blood lymphocytes and 40-50% of tonsil cells, so that there was a relationship between the percentage of killed cells and the proportion of T lymphocytes. However, when cells after cytotoxic treatment were assayed for rosette formation with sheep erythrocytes (a T-cell marker) 5-20% of viable rosette-forming lymphocytes were found. Therefore, this antiserum was cytotoxic for only 75-90% of T cells. From studies performed with antisera prepared against spleen and B-cell lines, we conclude that lymphoblastoid cells are antigenically different and deficient in comparison to normal B lymphocytes. In addition, cultured B-cell lines appear to be antigenically heterogenous, as shown by the cytotoxic activity remaining in antispleen and anti-B-cell lines sera after absorption with various numbers and types of lymphoid cell lines. After absorption with normal lymphocytes, an antiserum produced against chronic lymphatic leukemia cells had specific activity associated with 12 chronic lymphatic leukemia cells tested. Absorption of the same antiserum with leukemic cells from two patients showed that a certain degree of antigenic heterogeneity also exists among chronic leukemic lymphocytes.

The Wiskott-Aldrich syndrome. Results of transfer factor therapy.

12 patients with Wiskott-Aldrich syndrome were treated with therapeutic doses of transfer factor in an attempt to induce cellular immunity. Clinical improvement was noted after transfer factor therapy in 7 of the 12 patients treated. Because this disease has a variable course and temporary spontaneous improvement can occur, the observed improvement cannot necessarily be attributed to the transfer factor. However, in two patients repeated remissions consistently followed transfer factor administration on repeated occasions. This included freedom from infections, regression of splenomegaly, and clearing of eczema. An unexpected finding was a decrease in bleeding in 3 of the 10 patients who had bleeding. Conversion of skin reactivity was obtained in all seven patients who clinically seemed to respond to transfer factor. In vitro studies performed after the administration of transfer factor demonstrated that the lymphocytes of the patients now produced migration inhibitory factor in response to appropriate test antigens, but did not undergo increased radioactive thymidine incorporation in response to the same antigens. A defect in the monocyte IgG receptors has been found in certain patients with the disease, and the current study shows that all patients with defective monocyte IgG receptors responded to transfer factor, whereas only one patient with normal receptors showed any response. This test may thus prove to be useful in predicting the results of transfer factor therapy in patients with Wiskott-Aldrich syndrome, although evaluation of a larger series of patients will be necessary to confirm this point. We conclude that cellular immunity can be induced, that there appears to be clinical benefit in certain patients with Wiskott-Aldrich syndrome by the use of transfer factor, and that this mode of therapy warrents trial in these patients and others with defects of cellular immunity.

Digital ischemia and gangrene preceding renal neoplasm. An association with sarcomatoid adenocarcinoma of the kidney.

A 63-year-old woman had acute onset of rapidly progressive Raynaud phenomenon and digital gangrene. Prior to the detection of a sarcomatoid renal carcinoma, prominemt hypergammaglobulinemia, microhematuria, and weight loss were noted. Following nephrectomy, the patient showed improvement of the Raynaud phenomenon, with complete healing of digital ulcers and decrease of gama-globulin levels. Immunofluroescence studies demonstrated substantial deposits of IgG that lined the tumor cells in a linear and diffuse pattern. Electron-dense deposits were seen in the endothelium of arterioles int the tumor by electron microscopy. These findings suggest that antibodies to tumor antigens may have participated in the induction of digital vasculitis and Raynaud phenomenon.

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.

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.

The prognostic and therapeutic implications of DNA:anti-DNA immune complexes in systemic lupus erythematosus (SLE).

Serum samples serially obtained from 50 patients with systemic lupus erythematosus (SLE) were studied for antibody to deoxyribonucleic acid (DNA) and circulating DNA:anti-DNA complexes during the active and inactive phases of their disease. The patients were divided into four categories: Group I: six patients without clinical evidence of central nervous system (CNS) or renal involvement. Group II: three patients with CNS lupus. Group III: nine patients with normal urinalyses and glomerular filtration rates, but morphologic evidence of glomerular disease. Group IV: 32 patients with overt lupus nephritis. Elevated anti-DNA levels were observed in 16 of 18 patients (88 per cent) in groups I, II and III during active disease. This persisted in 14 (77 per cent) during remission. DNA:anti-DNA complexes were demonstrated in four of 18 (22 per cent) during active disease and disappeared in all but one patient with progressive disease. In 30 of the 32 patients (94 per cent) in group IV, DNA binding was increased during active disease; this persisted in 21 (70 per cent) despite remission. Complexes were observed in 25 of the patients in group IV (78 per cent) with active disease. In six of these patients, complexes have persisted; two have died, one has progressed to renal failure and the remaining three patients continue to manifest active disease. This study suggests that measurement of DNA:anti-DNA complexes provides a valuable additional index of disease activity and prognosis in SLE.

The effect of oxisuran on human immunological responsiveness.

Immunological function was evaluated in 9 patients who received oxisuran at a dose range of 5-90 mg/kg, for periods of 5-40 weeks. Bone marrow cytotoxicity and lymphopenia did not occur. Established humoral immunological reactions were unaffected by oxisuran. Only 6 of 19 previously positive skin tests reverted to negative. Primary cellular immune reactivity was markedly suppressed. Allogenic skin graft survival was prolonged to a mean of 30.7 days and only 2 of 9 patients were successfully sensitized to dinitrochlorobenzene and Keyhole limpet hemocyanin, respectively. Both IgG and IgM responses to primary typhoid immunization were inhibited. In vitro peripheral blood lymphocyte activity in phytohemagglutinin and mixed lymphocyte culture tests remained normal. These data suggest that oxisuran interferes with the afferent limb of the immune system and may thereby be clinically useful in human transplantation.

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.

Immunosuppressive therapy for severe chronic uveitis.

Twenty-five patients with severe, progressive, chronic uveitis who were poorly responsive or unresponsive to corticosteroid therapy received low-dose prednisone and cytotoxic immunosuppressive therapy. Azathioprine (2.0 to 2.5 mg/kg) or chlorambucil (6 to 8 mg) was combined with prednisone (10 to 15 mg) daily in a long-term therapeutic program. All 25 patients exhibited a therapeutic response. In 18 of 25 patients, complete quiescence of the inflammatory process was observed. The remaining seven patients showed a substantial decrease of uveitis with persistence of some inflammatory changes. Adverse side effects that resulted from this therapy were infrequent.

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.

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.

When autoimmune hemolytic anemia complicates chronic lymphocytic leukemia.

Autoimmune hemolytic anemia often develops in patients with chronic lymphocytic leukemia, particularly elderly women. It is heralded by a drop in the hematocrit, elevation of reticulocytes, development of jaundice, or a rise in the indirect fraction of serum bilirubin. Evidence of hemolysis supports the diagnosis, and a positive result of the Coombs test confirms it. Survival time is considerably shorter in patients who have both diseases than in those with chronic lymphocytic leukemia alone. Presenting symptoms in patients with the two diseases may include weakness, dizziness, fever, or hemorrhagic phenomena. If the anemia is severe, palpitations, otic pulsations, and cardiac decompensation are common. Physical examination may show enlargement of reticuloendothelial structures. On the other hand, some patients may be essentially asymptomatic. The hemolytic process must be treated as a separate entity, as even vigorous treatment of the leukemia often does not control it. Corticosteroid therapy is preferred, with splenectomy as a second line of defense. If the patient is not a good surgical risk, chemotherapy should be considered. Transfusions are usually incompatible but should be risked if progressive congestive failure, neurologic disturbance, angina, or signs of an impending infarct are present.