Effect of length of gestation on maternal cellular immunity to human trophoblast antigens

Maternal lymphocyte reactivity to human trophoblast antigens was studied in placentas of gestational ages 8 to 14 weeks and 32 to 34 weeks, respectively. Significant trophoblast lysis became apparent after 24 hours' incubation in the latter case compared with a time lag of 72 hours in the terminated gestations. Maternal cellular immunity, therefore, was not detected during the first 3 1/2 months of pregnancy, but was detectable by the time of parturition. The possible significance is discussed with respect to the antigenic stimulus and survival of the fetal allograft.     

Adjuvant activity of muramyl dipeptide derivatives to enhance immunogenicity of a hantavirus-inactivated vaccine

The adjuvant effect of two lipophilic derivatives of muramyl dipeptide (MDP), B30-MDP and MDP-Lys(L18), on the ability of an inactivated vaccine of B-1 virus (B-1 vaccine) to induce immune response against Hantavirus causing hemorrhagic fever with renal syndrome (HFRS) was examined. When mice were immunized subcutaneously (s.c.) twice at 2-week intervals with B-1 vaccine admixed with or without 100 micrograms mouse-1 of B30-MDP (B-1/B30-MDP) or MDP-Lys(L18) [B-1/MDP-Lys(L18)], mice immunized with B-1/B30-MDP as well as B-1/MDP-Lys(L18) showed significantly higher indirect fluorescent antibody (IFA) titers against HFRS virus than mice immunized with B-1 vaccine alone. Both mice treated with B-1/B30-MDP and B-1/MDP-Lys(L18) also exhibited significantly higher neutralizing antibody titers against HFRS virus than mice immunized with B-1 vaccine alone during 3-9 weeks after the primary immunization. The evaluation of antibody-producing cells by enzyme-linked immunospot (ELISPOT) assay on week 4 revealed that both MDP derivatives enhanced the number of HFRS virus-specific IgG1 and IgM antibody-producing cells. Furthermore, mice treated with B-1/B30-MDP as well as B-1/MDP-Lys(L18) showed a higher level of Th-2 type cytokines, IL-4 and IL-6, in sera than mice treated with B-1 alone. In an in-vitro analysis of T lymphocyte proliferation to baculovirus-expressed recombinant nucleocapsid protein (rNP) of Hantaan 76-118 strain, the splenocytes of mice treated with B-1/B30-MDP and B-1/MDP-Lys(L18) on week 4 showed a significantly higher proliferating activity than those treated with B-1 vaccine alone. In addition, when mice were immunized once with B-1 vaccine admixed with or without B30-MDP and MDP-Lys(L18) and followed by intrafootpad (i.f.) injection of B-1 vaccine on day 7, mice immunized with B-1/B30-MDP and B-1/MDP-Lys(L18) induced a higher delayed-type hypersensitivity (DTH) reaction than mice immunized with B-1 vaccine alone. These results suggest that B30-MDP and MDP-Lys(L18) are useful immunoadjuvants to enhance the ability of inactivated B-1 vaccine to induce a humoral and cellular response to HFRS virus.     

Evidence that cellular immune responses to soluble and membrane associated antigens are independently regulated during human schistosomiasis mansoni

The glucagonoma syndrome is a rare disorder characterized by weight loss, necrolytic migratory erythema (NME), diabetes, stomatitis, and diarrhea. We identified 21 patients with the glucagonoma syndrome evaluated at the Mayo Clinic from 1975 to 1991. Although NME and diabetes help identify patients with glucagonomas, other manifestations of malignant disease often lead to the diagnosis. If the diagnosis is made after the tumor is metastatic, the potential for cure is limited. The most common presenting symptoms of the glucagonoma syndrome were weight loss (71%), NME (67%), diabetes mellitus (38%), cheilosis or stomatitis (29%), and diarrhea (29%). Although only 8 of the 21 patients had diabetes at presentation, diabetes eventually developed in 16 patients, 75% of whom required insulin therapy. Symptoms other than NME or diabetes mellitus led to the diagnosis of an islet cell tumor in 7 patients. The combination of NME and diabetes mellitus led to a more rapid diagnosis (7 months) than either symptom alone (4 years). Ten patients had diabetes mellitus before the onset of NME. No patients had NME clearly preceding diabetes mellitus. Increased levels of secondary hormones, such as gastrin (4 patients), vasoactive intestinal peptide (1 patient), serotonin (5 patients), insulin (6 patients, clinically significant in 1 only), human pancreatic polypeptide (2 patients), calcitonin (2 patients) and adrenocorticotropic hormone (2 patients), contributed to clinical symptoms leading to the diagnosis of an islet cell tumor before the onset of the full glucagonoma syndrome in 2 patients. All patients had metastatic disease at presentation. Surgical debulking, chemotherapy, somatostatin, and hepatic artery embolization offered palliation of NME, diabetes, weight loss, and diarrhea. Despite the malignant potential of the glucagonomas, only 9 of 21 patients had tumor-related deaths, occurring an average of 4.91 years after diagnosis. Twelve patients were still alive, with an average age follow-up of 3.67 years.     

Immunostimulation with muramyl dipeptide and its desmethyl analogue: Studies of non-specific resistance to pulmonary blastomycosis in inbred mouse strains

N-acetyl-muramyl-L-alanyl-D-isoglutamine (MDP) protected against pulmonary blastomycosis when given prophylactically to BALB/c mice. Its desmethyl analogue (DM-MDP) had a similar effect. In C3H/HeJ, the effect was less marked. Early treatment after infection, with MDP and DM-MDP, had a modest effect in C3H/HeJ and BALB/c respectively, whereas late treatment had no effect in any mouse strain. No effect could be demonstrated with challenge sizes producing too lethal a model or minimal lethality, or in DBA/2J or young BALB/c mice. The effects in various strains do not correlate with differing effects on nonspecific immunostimulation in these strains. Immunostimulation with glycopeptides deserves further study in prophylaxis or therapy of fungal infection.     

Canine distemper virus DNA vaccination induces humoral and cellular immunity and protects against a lethal intracerebral challenge

We have studied the immune responses to the two glycoproteins of the Morbillivirus canine distemper virus (CDV) after DNA vaccination of BALB/c mice. The plasmids coding for both CDV hemagglutinin (H) and fusion protein (F) induce high levels of antibodies which persist for more than 6 months. Intramuscular inoculation of the CDV DNA induces a predominantly immunoglobulin G2a (IgG2a) response (Th1 response), whereas gene gun immunization with CDV H evokes exclusively an IgG1 response (Th2 response). In contrast, the CDV F gene elicited a mixed, IgG1 and IgG2a response. Mice vaccinated (by gene gun) with either the CDV H or F DNA showed a class I-restricted cytotoxic lymphocyte response. Immunized mice challenged intracerebrally with a lethal dose of a neurovirulent strain of CDV were protected. However, approximately 30% of the mice vaccinated with the CDV F DNA became obese in the first 2 months following the challenge. This was not correlated with the serum antibody levels.     

CD40 ligand/trimer DNA enhances both humoral and cellular immune responses and induces protective immunity to infectious and tumor challenge

CD40/CD40 ligand interactions have a central role in the induction of both humoral and cellular immunity. In this study, we examined whether a plasmid expressing CD40 ligand/trimer (CD40LT) could enhance immune responses in vivo. BALB/c mice were injected with plasmid expressing beta-galactosidase DNA with or without CD40LT DNA or IL-12 DNA, and immune responses were assessed. Mice vaccinated with beta-gal DNA plus CD40LT DNA or IL-12 DNA had a striking increase in Ag-specific production of IFN-gamma, cytolytic T cell activity, and IgG2a Ab. The mechanism by which CD40LT DNA enhanced these responses was further assessed by treating vaccinated mice with anti-IL-12 mAb or CTLA-4 Ig (CTLA4Ig). Production of IFN-gamma and CTL activity was abrogated by these treatments, suggesting that CD40LT DNA was mediating its effects on IFN-gamma and CTL activity through induction of IL-12 and enhancement of B7 expression, respectively. Physiologic relevance for the ability of CD40LT DNA to enhance immune responses by the aforementioned pathways was shown in two in vivo models. First, with regard to CTL activity, mice vaccinated with CD40LT DNA did not develop metastatic tumor following challenge with lethal dose of tumor. Moreover, in a mouse model requiring IL-12-dependent production of IFN-gamma, mice vaccinated with soluble Leishmania Ag and CD40LT DNA were able to control infection with Leishmania major. These data suggest that CD40LT DNA could be a useful vaccine adjuvant for diseases requiring cellular and/or humoral immunity.     

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.     

Experimental autoimmune uveo-retinitis (EAU): cellular immunity and humoral antibodies in the induction of ocular lesions and tolerance to retinal antigens

EAU is induced in guinea pigs by one inoculation into the foot-pad of a retinal extract in complete Freund's adjuvant. The evolution of the antibodies (complement fixation) is compared with the évolution of the disease (intensity evaluated by frequent ophthalmological examinations). The successful passive transfer of the disease by local injections of immune serum and the demonstration by immunofluorescence of immune complexes in the ocular tissues are arguments for the role of humoral antibodies in the induction of the disease. EAUmay be inhibited by repeated subcutaneous or intradermal injections of the antigen, either before or after the onset of the inflammation. These injections depress the delayed hypersensitivity and increase the titre of complement fixing and passive anaphylactic antibodies.     

Vaccine requirements for sustained cellular immunity to an intracellular parasitic infection

The humoral immunity induced by many viral and bacterial vaccines mediates protection that is maintained over a long period of time. In contrast, for other intracellular infections (such as with Leishmania major or Mycobacterium tuberculosis) for which cell-mediated immunity is required for protection, the mechanisms for developing durable responses after vaccination have not been well defined. Here we demonstrate that vaccination with plasmid DNA encoding a specific leishmanial antigen is more effective than leishmanial protein plus recombinant IL-12 in eliciting long-term immunity capable of controlling L. major infection. We also show that leishmanial protein plus IL-12 DNA produces an immunity that lasts much longer than does immunity elicited by leishmanial protein plus IL-12 protein, indicating that the persistence of IL-12 may be the essential determinant in maintaining durable cell-mediated immune responses for an intracellular parasitic infection.     

Antibody responses and protective immunity to recombinant vaccinia virus-expressed bluetongue virus antigens

The role of individual viral proteins in the immune response to bluetongue virus (BTV) is not clearly understood. To investigate the contributions of the outer capsid proteins, VP2 and VP5, and possible interactions between them, these proteins were expressed from recombinant vaccinia viruses either as individual proteins or together in double recombinants, or with the core protein VP7 in a triple recombinant. Comparison of the immunogenicity of the vaccinia expressed proteins with BTV expressed proteins was carried out by inoculation of rabbits and sheep. Each of the recombinants was capable of stimulating an anti-BTV antibody response, although there was a wide range in the level of response between animals and species. Vaccinia-expressed VP2 was poorly immunogenic, particularly in rabbits. VP5, on the whole, stimulated higher ELISA titers in rabbits and sheep and in some animals in both species was able to stimulate virus neutralizing antibodies. When the protective efficacy of VP2 and VP5 was tested in sheep, vaccinia-expressed VP2, VP5 and VP2 + VP5 were protective, with the most consistent protection being in groups immunized with both proteins.     

The effect of ascorbate on cellular humoral immunity in asthmatic children

Ten White children with bronchial asthma and exercise-induced bronchoconstriction were assessed immunologically before and 1, 3 and 6 months after the commencement of standard therapy supplemented with ascorbate 1 g/d. The tests of cellular immune function were neutrophil chemotaxis, phagocytosis and resting and stimulated nitroblue tetrazolium reduction, and lymphocyte mitogen-induced transformation. Humoral functions measured were secretory IgA, serum immunoglobulins, alpha 1-antitrypsin, C3, C4 and total haemolytic complement, antistreptolysin O (ASO) and C-reactive protein. Radio-allergosorbent testing to the common allergens Cynodon dactylon (grass), Dermatophagoides pteronyssinus (mite), house dust and cat epithelium was performed on each child before and 3 and 6 months after treatment. Two children had depressed neutrophil motility, 4 had depressed lymphocyte transformation, and 7 had elevated levels of ASO. These functions normalized after 6 months of ascorbate-supplemented therapy. Serum total IgE levels but not specific IgE levels were likewise reduced after 6 months of therapy. Reduced levels of serum alpha 1-antitrypsin were observed in 2 children, and remained unchanged throughout the study.     

Immunological responses from non-exposed donors to malaria antigens: implications for immunity and pathology

An approach to identification of epitopes suitable for vaccine development has been to locate regions of malaria target antigens that are recognized by individuals with clinical immunity. This has applied to identification of T- and B-cell epitopes. It is now realized, however, that T cells from individuals without prior exposure to malaria can respond to malaria parasites, malaria proteins, and peptides copying protein sequences. Such observations raise questions about which epitopes we should be targeting for vaccine development, but also challenge our understanding of immunological memory. Such responses from non-exposed individuals may also be important in expression of disease symptoms.     

The state of cellular immunity in women with a history of viral hepatitis

Overall sixty puerperants were examined with a history of viral hepatitis before true pregnancy has set in, with 50 healthy puerperants being controls. In women with prior viral hepatitis, the B-cell link of immunity was found out to be disordered, especially so postpartum, as evidenced by investigations designed to study the chief classes of immunoglobulin G, A, M in parturient women's blood sera and the postpartum complications patterns.