The effects of BCG on both cellular and humoral immunity during the early response to a hapten carrier complex.

Cell-mediated reactions to the carrier and antibody-mediated reactions to hapten and carrier were studied in guinea-pigs treated with a single i.v. injection of BCG at different intervals of time before immunization with two different doses of a hapten-carrier complex. The results clearly show that BCG-induced delayed hypersensitivity reactions to the carrier and decreased antibody synthesis to the hapten. It is proposed that BCG acts on a dispatcher cell which controls both cellular and humoral immunity.     

In vivo effect of levamisole on cellular and humoral immunity in normal chickens.

The effect of levamisole in vivo was studied on the PHA and Con A responses of chicken peripheral blood lymphocytes and on the in vivo antibody response to a thymus dependent antigen (BSA) and to a thymus independent antigen (Brucella abortus). Levamisole (0.25 mg/kg) increased significantly both the PHA and Con A responses of chicken blood lymphocytes. The antigens were given at the time of enhanced mitogenic responses and a significant increase was observed in both IgM and IgG antibodies to BSA. In contrast, no effect was obtained on antibody responses to Brucella abortus organisms. The results show that levamisole is able to enhance both humoral and cellular immune responses in normal chickens. The effect is probably mediated by the activation of the T cell function and effects only antibody responses to thymus dependent antigen. These findings confirm and extend the observations regarding the ability of levamisole to modulate immune responses.     

Maternal antibody inhibits both cellular and humoral immunity in response to measles vaccination at birth

Maternal antibody prevents the use of live, attenuated measles vaccine (LAV) before 6-9 months of age, but vaccinated 6-month-old infants can mount a T cell response. An infant macaque model was used to study the immune response to LAV in the newborn in the presence or absence of maternal antibody. Four newborn monkeys without detectable maternal antibody and 9 newborns with passive measles antibody were vaccinated with LAV. Only the infants without passive antibody seroconverted after vaccination and 3 of 4 of these infants also developed measles-specific interferon gamma+ T cells. The monkeys were challenged with wild-type measles virus at 5 months of age, and 7 of 9 infants vaccinated in the presence of passive antibody had systemic infection and skin rash, while 3 of the 4 infants vaccinated in the absence of passive antibody were protected from viremia and rash. This suggests that the newborn can respond to LAV but that maternal antibody suppresses the priming of both humoral and cellular immunity at birth.     

Interactions between sodium diethyl-dithiocarbamate and lysozyme during the immune response to a hapten-carrier complex

The effects of lysozyme and sodium diethyl-dithiocarbamate (DTC) were studied on antibody synthesis induced by immunization with a hapten-carrier complex. The immunomodulating effects of lysozyme could be partially reversed by DTC, a sulphur derivative which has been previously shown to modulate the immune response, probably at the macrophage level. The mechanisms whereby lysozyme and DTC modulated the immune response are discussed.     

The effect of levamisole on cellular immunity in multiple sclerosis.

The lymphocyte stimulation test has been standardized in a normal human population using four virus cell-associated antigens (VCAA): human embryonic lung cells infected with the LEC and Norrby strains of measles virus, mumps virus, and vaccinia virus. Following 1 week of treatment with the immunopotentiating drug levamisole, a group of multiple sclerosis (MS) patients was found to have increased lymphocyte stimulation responses toward VCAA and increased delayed hypersensitivity responses towards a battery of skin test antigens. No change in the percentage of short- or long-incubation E rosettes occurred. Measles haemagglutinin inhibition (HI) antibody titres measured before and after the entire course of levamisole therapy (12 weeks) did not change. The neurological status of five out of seven MS patients deteriorated while they were taking levamisole.     

Attempts to modulate the immune response to a hapten-carrier complex with various hapten-containing compounds.

The immune response to a hapten-carrier conjugate appears to be a complex phenomenon where reactions of the T-cell population are not restricted to the carrier and where the reactions of the B-cell population are not limited to the hapten determinant of the antigen molecule. To get a better understanding of the different cell interactions during the immune response to a hapten-carrier complex, the effects of immunogenic or tolerogenic injections of various hapten-containing compounds on the responses induced by immunization with the same hapten coupled to protein carriers were studied. The results indicate that T cells involved in delayed hypersensitivity and T cells involved in contact dermatitis could belong to distinct subclasses and confirm that hapten and carrier moieties of the antigen molecule could compete, probably at the macrophage level, for both delayed hypersensitivity to the carrier and antibody synthesis to the hapten.     

The suppressive effect of carrier priming on the response to a hapten-carrier conjugate

Carrier-primed cells, having some of the properties of T lymphocytes, have been found to inhibit the primary anti-hapten response of spleen cells to challenge with a hapten carrier conjugate. The antibody response of CBA/Ig^b spleen cells in irradiated CBA (Ig^a) recipients was measured by means of a radioimmunoassay using ¹²⁵I-labeled anti-Ig^b antibody. It was found that the primary anti-2,4,6-trinitrophenyl(TNP) response to TNP-KLH (keyhole limpet hemocyanin) was suppressed in recipient mice primed with KLH as compared with similarly treated unprimed or bovine serum albumin-primed recipients. This suppression was transferred by injection of 10⁸ spleen cells from CBA mice primed with KLH seven days beforehand, but not by injection of serum from such mice. The suppressive effect was abolished by treating the carrier-primed spleen cells with anti-T cell sera and complement before transfer. Priming with KLH seven days beforehand had only a small suppressive effect on the response to an unrelated antigen, DNP-ovalbumin, but there was marked suppression if KLH was again administered with the unrelated antigen. It is considered that the suppressive effect is specific in induction, but nonspecific in expression and that it is a manifestation of a homeostatic mechanism limiting the extent of the immune response.     

Contributions of humoral and cellular immunity to vaccine-induced protection in humans

Vaccines play a vital role in protecting the host against infectious disease. The most effective licensed vaccines elicit long-term antigen-specific antibody responses by plasma cells in addition to the development of persisting T cell and B cell memory. The relative contributions of these different immune cell subsets are context-dependent and vary depending on the attributes of the vaccine (i.e., live/attenuated, inactivated, and subunit) as well as the biology of the pathogen in question. For relatively simple vaccines against bacterial antigens (e.g., tetanus toxin) or invariant viruses, the immunological correlates of protection are well-characterized. For more complex vaccines against viruses, especially those that mutate or cause latent infections, it is more difficult to define the specific correlates of immunity. This often requires observational/natural history studies, clinical trials, or experimental evaluation in relevant animal models in order for immunological correlates to be determined or extrapolated. In this review, we will discuss the relative contributions of virus-specific T cell and B cell responses to vaccine-mediated protection against disease.     

The effects of calcitonin and colchicine on the cellular response to diphosphonate.

The mechanism by which diphosphonates inhibit bone resorption remains speculative; however, the osteoclast appears to be selectively affected by the drug. This study examined the effects off diphosphonate on osteoclasis in bones treated concomitantly with agents which reduce the osteoclast ruffled border, calcitonin and colchicine. Dichloromethylene diphosphonate, calcitonin, and colchicine inhibited parathyroid-hormone-stimulated bone resorption, as indicated by a significantly reduced release of 45Ca from prelabelled long bones. Quantitative and qualitative histological analyses of osteoclasts indicated differences among effects resulting from agents. Only bones treated with diphosphonate demonstrated a majority of osteoclasts with degenerative appearance; colchicine-treated bones exhibited many spherulated cells with cytoplasmic blebs. The number of normal osteoclasts in calcitonin-treated bones was the same as in controls and decreased with diphosphonate and colchicine treatment. All inhibitory agents reduced the number of nuclei per osteoclast; furthermore, colchicine effected an additional significant reduction, as compared with diphosphonate and calcitonin. The number and frequency of abnormal osteoclasts was increased by diphosphonate, but unaffected by colchicine and calcitonin. The addition of calcitonin, but not colchicine, to diphosphonate-treated bones decreased the incidence of abnormal osteoclasts. Although both calcitonin and colchicine are known to reduce the osteoclast ruffled border, this study has shown differences between the morphological effects of the 2 agents which presumably reflect differences in their mode of action and their interaction with diphosphonate.     

The effects of perfluorodecanoic acid (PFDA) on humoral, cellular, and innate immunity in Fischer 344 rats.

The in vivo effects of perfluorodecanoic acid (PFDA) exposure on antibody production, delayed type hypersensitivity (DTH), and natural killer (NK) cell activity were determined. Fischer 344 rats were injected with PFDA (20 mg/kg or 50 mg/kg, 8 days or 30 days prior to sacrifice) and were immunized with keyhole limpet hemocyanin (KLH). Pair-fed and ad libitum-fed control rats were included to evaluate effects of PFDA-induced anorexia. KLH-specific IgG2a production was significantly decreased (p < 0.05) in PFDA-treated rats when compared to ad libitum-fed and pair-fed controls at 8 days but not at 30 days following PFDA treatment. The DTH response of PFDA-treated rats was decreased 8 days and 30 days after PFDA treatment when compared to ad libitum-fed and pair-fed controls, however, the decrease was not statistically significant. NK activity 30 days after PFDA treatment was significantly elevated (p < 0.05) when compared to ad libitum-fed controls, but pair-fed controls had similarly elevated NK activity. NK activity at 8 days after PFDA treatment was not significantly altered. In conclusion, PFDA has been demonstrated to have immunomodulatory effects, some of which may be associated with drug-induced anorexia.     

The early cellular and humoral immune response to primary and booster oral immunization with cholera toxin B subunit

The immune response to cholera toxin B subunit given orally was studied in 13 human volunteers. A serum IgG and IgA antitoxin response was observed, which was boosted by a second immunization. Using an immunospot assay, cells spontaneously secreting anti-toxin IgG and IgA, but not IgM appeared transiently in the blood after immunization. There were 105 IgG- and 87 IgA-secreting cells per 2 x 10(6) mononuclear cells 7 days after the first immunization, and 282 IgG- and 413 IgA-secreting cells 5 days after the second immunization. A polyclonal increase in total IgM-secreting cells was observed. Few anti-toxin-secreting cells were observed in the bone marrow at the peak of the circulating cell response, which could be accounted for by contamination of the sample with peripheral blood, suggesting that the bone marrow is not a significant site of anti-toxin-secreting cells after oral immunization.     

The immunosuppressive effect of mycoplasma infection: I. Effect on the humoral and cellular response

Mycoplasma-induced immunosuppression in rats was demonstrated with Mycoplasma arthritidis strain PN. Immunosuppression involving the humoral antibody response was complete or partial when mycoplasma was injected concurrently with the antigen. Mycoplasma did not interfere with the antibody response when injected after primary immunization.

Inhibition of blast transformation was shown to occur in lymphocytes derived from rats infected with the above mycoplasma. The inhibition was partial or complete depending on the interval between the infection and the time when the lymphocytes were taken from the animal, and blast transformation reverted to normal when the infection was over.

Although the question of mechanism remains open, it was concluded that immunosuppression might be the result of the effect of M. arthritidis on a particular population of cells.

     

Prolonged administration of antithymocyte serum in mice. I. Observations on cellular and humoral immunity

A colony of 400 CBA/He mice was divided into three groups: (a) mice injected continually throughout life with rabbit antimouse thymocyte serum (ATS), (b) mice treated in the same manner with normal rabbit serum (NRS), and (c) mice left untreated.

The cellular immune competence of all groups was tested by the transplantation of allografts or rat xenografts, by testing the ability of their lymphoid cells to mount a graft-versus-host reaction, by measuring the in vivo response of their lymphocytes to oxazolone skin-painting and the in vitro response to phytohaemagglutinin, and finally by measuring the organ distribution of the θ-positive, thymus-dependent lymphocyte population. Determinations were made of the antibody responses to sheep erythrocytes, allografts and rat xenografts, bovine serum albumin, keyhole limpet haemocyanin, and polyoma virus.

The ATS-treated mice grew and reproduced normally and did not succumb to bacterial infections. Polyoma virus, probably introduced in the rabbit serum, induced tumours in only some of the ATS-treated mice. Only two lymphomas (0·8%) occurred in this same group; tumours were not seen in the other groups.

These results do not support any hypothesis which attributes to lymphocytes a non-immunological function, nor do they support a simple form of the immunological surveillance theory in relation to cancer. Several possible explanations for the increased incidence of tumours in transplant patients are proposed, which take into account the difficulty experienced in this study in abrogating a `cellular immune response' with antilymphocytic serum alone.

     

Modulation of delayed-type hypersensitivity and cellular immunity to microbial vaccines: effects of cyclophosphamide on the immune response to tularemia vaccine.

Treatment of guinea pigs with cyclophosphamide before immunization with killed tularemia vaccine in Freund incomplete adjuvant produced a prolongation and intensification of delayed-type hypersensitivity and in vitro lymphocyte transformation reactions to tularemia antigen. Such reactions resemble those ordinarily associated with the administration of live tularemia vaccine, killed vaccine in Freund complete adjuvant, or recovery from natural infection. The immunopotentiation lasted longer than that seen previously in other antigenic systems with this drug and was dependent on the dose of vaccine used. More intense delayed skin reactivity could be transferred into normal controls by cells from immunized donors pretreated with cyclophosphamide than by cells from immunized donors that were not pretreated.     

Characterization of humoral and cellular immunity to rubella vaccine in four distinct cohorts

Although vaccination campaigns have significantly reduced the global burden of rubella disease, there are still regional outbreaks and cases of congenital rubella syndrome. Rubella vaccination elicits a strong humoral as well as cellular response. The relationship between these two measures in response to rubella vaccine is poorly understood. We have previously reported no correlation between rubella-virus-specific cytokine secretion and IgG antibody levels after rubella vaccination. In the current study, we extend our previous work to report correlations between secreted cytokines and functional neutralizing antibodies after rubella vaccination in four distinct cohorts. There was evidence of significant differences (p < 0.05) in rubella-virus-specific humoral and cellular responses between cohorts. When investigating relationships between rubella-vaccine-specific humoral and cellular immunity, we observed a significant correlation between neutralizing antibodies and IFN-γ (r _s  = 0.21, p = 0.0004). We also observed correlations in subjects with extreme humoral immune phenotypes and IFN-γ levels in two of the four cohorts (r _s  = 0.32, p = 0.01; r _s  = 0.36, p = 0.01, respectively). These findings indicate that there is a high level of heterogeneity in rubella-specific immune responses between study populations. We believe that the novel correlation discovered between IFN-γ and neutralizing antibody titers will give future insight into the functional mechanisms of immunity induced by rubella virus and other live viral vaccines.     

Effect of indomethacin in vivo on humoral and cellular immunity in humans

We studied the effect of indomethacin on intradermal skin testing and antibody responses in humans. Since we and others have shown that prostaglandins are suppressor cell mediators, it was probable that in vivo inhibition of prostaglandin synthesis might enhance the humoral and/or cellular immune response. Administration of indomethacin (Indocin) in a dosage of 100 mg/day to 15 normal men and women resulted in a significantly increased antibody titer to A-Victoria (P less than 0.025) as compared with age- and sex-matched controls. There was no difference in titer to A-New Jersey. Since 90% of the subjects had antibody titers to A-Victoria before inoculation, whereas none had detectable titers to A-New Jersey, we interpret this data as suggesting that indomethacin enhances the secondary but not the primary humoral immune response. Indomethacin administration did not alter the intradermal skin test responses.     

Modulation of cellular and humoral immunity, and disease manifestation during onset of patency in Brugia pahangi-infected dogs.

Recently, it has become possible to obtain as predicted disease manifestation in selectively bred dogs infected with the naturally occurring lymphatic nematode, Brugia pahangi. In this study, an attempt was made to correlate limb oedema with dynamic changes in immune cell responses occurring in the lymph node at the site of infection during onset of patency. Three litters of dogs were selectively bred; one for the expression of clinical disease, one for the lack of expression of clinical disease and one was of non-specific phenotype. Lymph node cells from 10 of 11 dogs showed a parasite-specific proliferative response at 4-6 weeks post-infection (p.i.), before the onset of patency. In six of 11 dogs, a loss of proliferative response to BpA in the infected node cells was detected around the time of onset of patency. In contrast, there was no reduction in the proliferative response to the mitogen phytohaemagglutinin (PHA). The proliferative response to BpA by unresponsive node cells could be restored by addition of substimulatory amounts of murine or human recombinant interleukin-2 (IL-2) to the culture medium. However, there was no correlation between the proliferative response of lymph node cells from infected limbs and the expression of clinical disease. Similarly, when in vitro parasite-specific antibody production by infected lymph node cells was examined, antibody production manifested by all dogs at 5 weeks p.i. was markedly changed at 8 weeks p.i., but these changes did not correlate with clinical disease. This lack of correlation indicates that the immune response to lymphatic filarial infection, as measured in this study, does not necessarily result directly in disease manifestation, and that other genetically determined factors may influence both the parasite-specific immune response and the clinical outcome of infection.     

The effect of E-N-l-trimethyllysine (TML) on the humoral and cellular immune response

E-N-l-Trimethyllysine glutamate (TML) influences the humoral and cellular immune response of mice. Chronic pre- and post-treatment (100 mg/kg/day, 5 times) transitionally increased the anti-SRBC haemagglutinin titre of female CBA mice. After 400 r whole body irradiation, TML treatment accelerated the normalization of the haemagglutinin level. TML treatment prolonged the life-span of BDF₁ hybrid mice that had first been immunized and then inoculated with L₁₂₁₀ cells. TML diminished the delayed type hypersensitivity mice and dosse-dependently decreased the spontaneous (SLMC) and antibody-dependent (ADCC) cytotoxicity of healthy human lymphocytes,in vitro. As a low molecular weight immunomodulant, TML may also be considered as a therapeutic tool.