Nonspecific Immunostimulation Research Articles

Influence of immune status on virus-derived transplantable hepatoma in chickens.

The transplantable MC-29 virus-derived hepatoma is a suitable model for studying the influence of immune status on virus-derived hepatomas in chickens. It was found that both humoral and cellular immunologic reactions have a role in the pathogenesis of virus-derived hepatomas and that virus-derived hepatomas can be influenced by nonspecific immunostimulation. The lymphoid system was profoundly altered in hepatoma-bearing chickens; this cannot be neglected when studying correlations between immune reactions and carcinogenesis. Profound changes were also observed in protein synthesis and the steroid receptor system of hepatoma-bearing chickens compared to healthy birds; this also complicates the understanding of the role of immune mechanisms in carcinogenesis.

Active immunotherapy of friend virus-induced erythroleukemia and its spontaneous regression

We have tested the effects of specific and nonspecific immunostimulation on the spontaneous regression and recurrence of erythroleukemia induced by a strain of the Friend murine leukemia virus complex, RFV. Subcutaneous inoculation of mice with UV-irradiated allogeneic leukemic spleen cells (LSC) protected against subsequent virus challenge. RFV-leukemic mice injected with LSC into subcutaneous BCG-primed sites had a significantly increased incidence of leukemia regression. When leukemic mice received BCG or LSC alone or normal allogeneic spleen cells (NSC) in place of LSC the incidence of regression was not different from that recorded in untreated controls. A single treatment of recently regressed mice with LSC given into BCG-primed sites prolonged the disease-free period, while LSC alone, BCG alone, or NSC had no such effect. Our data support an immunological basis for spontaneous regression of erythroleukemia and for maintenance of the regressed state. This system provides a model for testing the efficacy of immunotherapeutic protocols for maintenance of leukemia remission and tumor dormancy.

The Use of Levamisole in Atopic Dermatitis

Levamisole hydrochloride, a nonspecific immunostimulant, was given to 30 children with atopic dermatitis (AD) in a double-blind manner during an eight-month period. Clinical course findings, including intradermal reactions to tuberculin, candidin, and streptokinase-streptodernase; sensitization to dinitrochlorobenzene; periphal blood T- and B-lymphocytes; in vitro lymphocyte transformation with phytohemagglutinin; and serum levels of IgM, IgG, IgA, and IgE, were noted every two months. Fifteen children completed the study. Neither the clinical course nor the immunologic values showed substantial differences between the levamisole-treated and the placebo group. Our experience with levamisole in AD is disappointing.

The antileukemic effect of systemic non-specific BCG-immunostimulation vs systemic specific immunostimulation with irradiated isogeneic leukemic cells

The antitumoral effect of BCG has been compared to the antitumoral effect of injections of irradiated isogeneic leukemic cells in a transplantable, murine ascites leukemia. It was found that irradiated tumor cells in doses of 10 7 or 10 9 cells per injection (either s.c. or i.p.) induced prolongation of mean survival time and increased the percentage of cured mice. The effect of irradiated cells was highest with s.c. injections and an effect was observed only in mice inoculated with 10 2 or 10 3 living leukemic cells. BCG had only beneficial effect when given i.v. and only in a dose of 7 × 10 6 viable units per injection. Lower doses of BCG had no effect compared to controls and higher doses given i.v. or i.p. enhanced tumor growth. BCG injected i.v. may induce a cure in mice inoculated with 10 2−10 5 living leukemic cells. Spontaneously cured mice were highly susceptible to a second tumor inoculum containing a tumor cell number only one decade higher than the first inoculum. In contrast, immunostimulated mice rejected inocula 2–3 decades above first inoculum. Histologic examination of organs from mice cured either spontaneously or by immunostimulation revealed that BCG induced markedly histiocytic proliferation and infiltration in spleen, thymus, lymph nodes, liver, and lungs, whereas otherwise cured mice had no such lesions.

Transfer factor treatment of chronic mucocutaneous candidiasis: Requirement for donor reactivity to Candida antigen

Dialyzable transfer factor in conjunction with amphotericin B was used in the treatment of a patient with mucocutaneous candidiasis in a longitudinal controlled study over a 2.5-year period. Amphotericin B treatment alone produced a 3-week remission. Transfer factor from Candida-negative donors could not maintain this remission while transfer factor from donors with strong delayed hypersensitivity to Candida antigen could maintain an amphotericin B-induced remission. Further, this clinical response to transfer factor correlated with the appearance of a positive delayed hypersensitivity skin test to Candida antigen and the production of macrophage migration inhibitory factor (MIF) by the patient's lymphocytes when stimulated by this antigen. This observation supports the hypothesis that successful transfer factor therapy is the result of an antigenspecific conversion from the unreactive to the reactive state and not of nonspecific immunostimulation.

Immunostimulation before chemotherapy in cancer treatment

Summary Synergism between chemotherapy and immune responses has been evidenced in animals and man. In addition, non-specific immunostimulation seems to increase the efficiency of anticancer chemotherapy. Up to now most of the clinical trials have been conducted applying immunoadjuvants after initial chemotherapeutic treatment. Since presensitized immunocompetent cells are more radio- and chemo-resistant than non-stimulated lymphocytes, a trial of immunostimulation before chemotherapy is based on rational experimental basis. Such program, activated in humans during 1976, is conducted according to the following general scheme: o 1. Chemotherapy alone 2. Chemotherapy followed by BCG and recycle 3. Chemotherapy preceded and followed by BCG and recycle. Protocols for breast, lung, colorectal and ovarian cancer treatment are described.

Adjuvant Protection against Bacterial Infection in Granulocytopenic Mice

The hypothesis that the induction of nonspecific resistance to infection by immunostimulation prior to drug-induced granulocytopenia would afford increased protection to subsequent bacterial challenge was tested in a murine model of infection with Pseudomonas aeruginosa or Staphylococcus aureus in mice rendered granulocytopenic with cyclophosphamide. Prior intraperitoneal immunostimulation of mice with complete Freund's adjuvant (CFA) or Mycobacterium bovis (Bacille Calmette-Guèrin; BCG) increased the 50% lethal dose in mice challenged subcutaneously with P. aeruginosa, but only CFA protected against challenge with S. aureus. The degree of protection was 1-2 log 10. Corynebacterium parvum provided no protection against infection with P. aeruginosa. The protective effect observed with CFA and BCG substantiates our hypothesis and indicates that nonspecific immunostimulation may be of value in protection of granulocytopenic patients from opportunistic infections.

The Effect of BCG on Experimental Cutaneous Leishmaniasis in Mice

Abstract The effect of administration of live Bacillus Calmette-Guerin (BCG), a nonspecific immunostimulant, on the course of experimental cutaneous leishmaniasis in mice was investigated. BALB/c mice were injected in the footpad with Leishmania tropica, NIH S-strain; in mice that were not pretreated with BCG this produced a reproducible fatal infection characterized by local inflammation, regional lymphadenopathy, and dissemination of parasites with hepatosplenomegaly. In mice that were pretreated with BCG and similarly infected with L. tropica there was a reduction in the severity of cutaneous disease and a significant (p < 0.005) decrease in mortality without evidence of visceralization.

Effect of immunosuppression or immunostimulation on the growth rate of a lymphoid and of a myeloid leukemia in mice

The influence of immunosuppression or immunostimulation on the growth rate of a lymphatic and of a myeloid murine leukemia has been investigated in syngeneic host-tumour relation. Immunosuppression by chemotherapy or X-rays, induced before transplantation of leukemia cells, did not change the survival time of the animals. Treatment with the immunosuppressive drug cortisone which is not cytostatic for these leukemias, if instituted after the transplantation of malignant cells, enhanced the growth rate of the lymphatic leukemia. Nonspecific stimulation with Corynebacterium parvum induced resistance to a graft of lymphatic leukemia in a majority of the mice, but only slowed the growth rate of myeloid leukemia, without preventing death. Immunosuppressive treatment, given before C. parvum, completely blocked the induction of resistance, and if given after C. parvum, abolished the established resistance to lymphatic leukemia. Thus, the danger of immunosuppression accompanying chemotherapy may lie in its abrogating the protective effects of nonspecific immunostimulation.

BCG in the immunotherapy of malignant lymphomas

The effectiveness of a nonspecific immunostimulation in related human or animal diseases incited us to do a study of nonspecific immunotherapy by BCG in Hodgkin's disease, and then in other malignant lymphomas. Seventy patients, each one fulfilling at least 2 criteria of poor prognosis, were initially put in complete remission by a combination of radio-chemotherapy, followed by a reinforcing chemotherapy. These patients were then randomized into two groups. The first group received no further treatment; the second received BCG in weekly cutaneous scarifications. Eight patients were excluded from the study. The rate of relapses is significantly lower in the treated group. The results are discussed. Other therapeutic studies are necessary to fix the indications and modalities of this immunotherapy.

In vitro evidence for increased cellular immunity to lung cancer antigen during Levamisole immunotherapy

Levamisole, a potentiator of cell-mediated immunity, has been reported to increase survival in patients with resectable carcinoma of the lung. Cell-mediated immunity can be measured in vitro by the leukocyte migration inhibition test. We have previously reported that this test detects cell-mediated immunity to human lung tumor antigens. In the present studies, patients with lung cancer were treated with Levamisole. Their leukocytes were evaluated in the leukocyte migration inhibition assay before, during, and following Levamisole therapy. Small increases in cell-mediated immunity were observed when patients had a high pre-existing tumor immunity. When tumor-associated reactivity was absent prior to therapy, larger increases were measured. Although Levamisole is a nonspecific immunostimulant, these data indicate that in vitro anti-tumor immune responses are enhanced by Levamisole therapy. Augmentation of cell-mediated immunity to tumor antigens may explain the clinical benefits of Levamisole therapy.

Nonspecific immunotherapy of malignant tumors.

At present, nonspecific immunotherapy of malignant tumors seems to be the most promising among immunotherapeutic modalities. Potent nonspecific immunostimulants, Bacillus Calmette-Guerin (BCG) and Corynebacterium parvum, exhibit an antitumor activity in experimental animals, which is commonly manifested by reduced tumor growth and sometimes by complete regression of tumors. Antitumor effectiveness of these bacteria is largely related to tumor immunogenicity and host immunocompetence. Recently, BCG has frequently been used for clinical immunotherapy and has provided therapeutic benefit in many instances, particularly when combined with chemotherapy, radiotherapy or surgery. Clinical experience with C. parvum is so far limited.

The role of nonspecific immunotherapy in the treatment of breast cancer.

Although many oncologists and immunologists at present consider the study and manipulation of specific immunity to be primordial, we have devoted most of our efforts over the past 8 years to nonspecific im-munostimulation in cancer patients for the following reasons.KeywordsBreast CancerAdvanced Breast CancerActuarial SurvivalCorynebacterium ParvumNonspecific ImmunotherapyThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Intralymphatic injection of BCG into rhesus monkeys.

Since the route of administration of BCG may have an important function in immunotherapy, we investigated intralymphatic administration to direct BCG to the lymph nodes. Multiple injections of high doses of BCG were administered to 6 rhesus monkeys via the dorsal lymphatics of the lower limb. A suppurative lymphadenitis was observed along the lower limb and in the inguinal area in 5 of the 6 monkeys. However, many of the complications reported with other routes of administration were not observed. Granulomatous reactions and histiocytic responses developed in lymph nodes on the injected sides of the pelvis and distant nodes as well as in the liver. The intralymphatic route is the method by which high doses of nonspecific immunostimulants were delivered to regional lymph nodes. The efficacy of this approach remains to be established in tumor-bearing animals and humans.

Immunologic Reconstitution in Man—Present Status

Recent advances in immunobiology have shed new light on our understanding of the essential role of immunity as it relates to body economy. Immunity, once thought to be the primary defense mechanism against microbial infection, appears to have a much broader function--recognition and elimination of foreign bodies and preservation of the integrity of the individual. As our understanding of the pathophysiology of the immune system became more clear, immunologic reconstitution emerged as a new, promising mode of treatment for a variety of diseases with immunodeficiency. Bone marrow transplantation, thymus transplanation, transfer factor therapy, infusion of leukocytes, BCG vaccination, and other specific or nonspecific immunostimulants have been tried, with dramatic beneficial results in some instances. Although still in its infant stage, this form of treatment appears to have great potential and wide application in the prevention and treatment, not only of primary immunodeficiency, but also of many other diseases such as cancer, the so-called autoimmune diseases, and even aging.

The rationale of immunostimulation procedures in the therapeutic approach to malignant melanoma of the skin.

Thirty three patients with malignant melanoma found in different clinical stages of their disease are followed up for a period of two and a half years for survival or changes in the clinical status. Immunodiagnostic tests have determined their humoral and cellular reactivity. When negative, autoimmunization with autologous irradiated melanoma cells and/or BCG nonspecific immunostimulation has been undertaken with the aim to boost the production of tumor specific cytotoxic antibodies and mobilize cellular immunity. The following results have been recorded: all patients found in the stage of generalized disease have perished regardless of immunostimulation. Nevertheless, they have displayed three phenomena witnessing host response: cutaneous flare surrounding skin deposits, diminishing or subsidence of pulmonary metastases, partial or complete regression of subcutaneous metastatic deposits. Patients with hematogenic disseminated single or few deposits are alive after radical surgery and immunostimulation. Cases of localised disease: primary or primary with regional metastases have perished or become generalized when no immunostimulation has been undertaken; immunostimulated patients are doing well with no residual disease after radical surgery. A scheme of combined treatment of malignant melanoma on the background of immunostimulation procedures is suggested.

Immunotherapy of cancer: immunospecific rejection of tumors in recipients of neuraminidase-treated tumor cells plus BCG.

Firmly established methylcholanthrene fibrosarcomas in syngeneic mice will totally disappear if the hosts are treated with living tumor cells that have been exposed to Vibrio cholerae neuraminidase in vitro. The effect is magnified by the simultanieous injection of a nonspecific immunostimulant, BCG. The rejection of the methylcholanthrene tumor is immunospecific and can be induced only with tumor cells, treated with Vibrio cholerae neuraminidase, identical in type with the growing tumor.