Maternal antibodies against tetanus toxoid do not inhibit potency of antibody responses to autologous antigen in newborn rhesus monkeys

Background

Our previous study suggested newborns have competent immune systems with the potential to respond to foreign antigens and vaccines. In this study, we examined infant immune responses to tetanus toxoid (TT) vaccination in the presence of maternal antibody to TT.

Methods

We examined changes in plasma levels of tetanus toxoid‐specific IgG1 (anti‐TT IgG1) in a total of eight infant rhesus macaques from birth through 6 months of age using a commercial Monkey Anti‐TT IgG1 ELISA kit.

Results

A significant correlation between anti‐TT IgG1 levels in vaccinated dams and their paired newborn infants was detected in control (non‐vaccinated) infants as previously reported. Maternal anti‐TT IgG1 levels declined rapidly within 1 month of birth in non‐vaccinated infants (n=4). In four infants vaccinated with TT at birth, we found two had rapid and robust antibody responses to vaccination. Interestingly, the other two first showed declining TT antibody levels for 2 weeks followed by increasing levels without additional vaccine boosts, indicating all four had good antibody responses to primary TT vaccination at birth, despite the presence of high levels of maternal antibodies to TT in all four infants.

Conclusions

Our data indicate that newborn macaques have competent immune systems that are capable of generating their own primary antibody responses to vaccination, at least to tetanus antigens. Maternal antibodies thus do not significantly impair antibody response to the vaccination, even when received on the day of birth in infant rhesus macaques.     

Delayed dispersal and elevated monoaminergic activity in free-ranging rhesus monkeys

Male rhesus monkeys typically disperse from their groups of birth when they are between 3 and 5 years of age. Some males, however, delay dispersal from their natal groups until after they are 5 years old. The current study evaluated central monoaminergic neurotransmitter activity as a potential correlate of such “delayed” dispersal among 54 randomly selected adolescent and adult male rhesus monkeys (Macaca mulatta) captured on Cayo Santiago during an annual trapping season. Specifically, cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA, a serotonin metabolite), 3-methoxy-4-hydroxyphenylglycol (MHPG, a norepinephrine metabolite), and homovanillic acid (HVA, a dopamine metabolite) were compared in monkeys 60 months of age or more that had either dispersed (n = 33) or were still in their natal groups (n = 5). The monkeys still in their natal groups had higher CSF concentrations of both 5-HIAA and HVA (but not MHPG) than did the animals that had emigrated (Ps < 0.05). Subsequent analysis indicated that only 5-HIAA independently differentiated dispersing monkeys from delayed dispensers. Of monkeys less than 60 months of age (n = 16), only two had dispersed from their natal groups; in this age class, there were no significant differences between dispersing and natal individuals in any CSF monoaminergic metabolite (all Ps = NS). Finally, there was no difference in the CSF 5-HIAA concentrations of the five delayed dispersers and those of younger animals (P = NS), suggesting a failure to experience the frequently reported adolescent decline in serotonergic activity. In contrast, the CSF 5-HIAA concentrations of the dispersing animals were lower than those of the younger animals (P < 0.05), consistent with either an agerelated decline or an effect of dispersal per se. © 1995 Wiley-Liss, Inc.     

Delayed cutaneous hypersensitivity reaction to crude and semi-purified tumor extracts in cancer patients

Summary A positive delayed cutaneous hypersensitivity reaction (DCHR) was observed to only one of five KCl soluble extracts from as many different tumoral kidneys in nine of 11 patients with kidney cancer. None of the autologous normal renal tissue extracts gave a positive reaction. SDS-PAGE analysis showed a predominant component with a molecular weight corresponding to that of serum albumin in all the four negative cancer extracts. Lipoproteins and serum albumin were removed by ultracentrifugal flotation on KBr and by affinity chromatography on antiserum albumin (-HSA), respectively, from one of the negative crude extracts. KCl extract, F₂ fraction of KBr, and unbound material from the -HSA column were injected simultaneously into nine patients with renal cancer. Positive DCHRs were seen to the three extracts in no patients, in three, and in eight, respectively. The -HSA unbound fraction was positive in three of 13 patients with tumor at a site other than the kidney. The same extraction procedure was applied to normal autologous kidney tissue, and positive reactivity was observed in one of eight and three of nine patients with kidney cancer to the F₂ and -HSA unbound fractions, respectively. An aliquot of KCl tumor extract was passed through the -HSA column without the preliminary flotation on KBr, and the unbound fraction was positive in eight of nine patients with kidney cancer and in eight of twelve patients with other types of tumor. Three different melanomas were extracted in the same way and an increased percentage of DCHRs was found after removal of lipoproteins and HSA in melanoma patients. This reactivity, however, was not histologically related since patients with tumors other than melanoma reacted as well as melanoma patients. These data indicate that the removal of lipoproteins and HSA from crude tumor extracts may unmask or increase an existing antigenicity. The tumor-type-related experiments, however, suggest that these biochemical procedures are useful for kidney tumors but not for melanomas.     

Recall antigen delayed-type hypersensitivity skin testing: standardization of self-reading by patients

Summary In order to evaluate a self-reading system for the measurement of immunocompetence in cancer prognosis, a battery of delayed-type hypersensitivity skin tests with antigens including dermatophytin, candida, Varidase (streptokinase-streptodornase), mumps, and purified protein derivative (PPD) was administered to 50 cancer patients. The resulting erythema and induration were read by both technicians and patients at 24 and 48 h after placement of the tests. In addition, another group of 85 cancer patients received two identical candida skin tests placed at the same time on either the same or the opposite arm. The results from these two groups of patients indicated that patients' readings correlated well with technicians' readings, with most of the correlation coefficients being greater than 0.8. The weakest correlations were with antigens producing a large response. There was significant variability in the two identical simultaneously placed skin tests, and the correlation coefficients were much lower. The relevance of these data to serial skin testing is discussed.     

Failure to expand influenza and tetanus toxoid memory T cells in vitro correlates with disease course in SIV infected rhesus macaques

Marked decreases in influenza (flu) and tetanus toxoid (T.T.) antigen specific CD8(+) and CD4(+) T cell memory responses were noted shortly after SIV infection in monkeys that go on to develop clinical disease within 18 months (normal progressor, NP) following SIV infection but not in monkeys that remain asymptomatic >3 years post SIV infection (long-term nonprogressor, LTNP). While PBMCs from NP and LTNP monkeys demonstrate both low and high avidity flu and T.T. specific CD8(+) and CD4(+)T cell immune responses prior to SIV infection, the PBMCs from NP but not LTNP fail to generate high avidity T cell responses post SIV infection. This failure to generate high avidity T cell responses in vitro correlated with increased apoptotic cell death in PBMC cultures from NP animals. Since high avidity antigen specific CTLs have been shown to be most efficient in eliminating viral infections, the present finding has important implications for the evaluation of the level of immune reconstitution following various modalities of therapy in HIV-1 infected patients.     

Aotus monkeys: their great value for anti-malaria vaccines and drug testing

Non-human primates represent a valuable resource for testing potential vaccines candidates and drugs for human use. Malaria remains one of the greatest burdens for the humanity represented by approximately 500 million new clinical cases per year worldwide and at least two million deaths caused annually. Additional control measures such as vaccines and new anti-malarial compounds are therefore urgently needed. Safety and protective efficacy studies in animal models are critical steps for vaccines and drugs development and primate models are probably the most appropriate for this purpose. Although Aotus genus provides several species susceptible to both Plasmodium falciparum and Plasmodium vivax, having different susceptibility to malaria, Aotus lemurinus griseimembra represents the best current malaria primate model because of its high susceptibility to infection by blood forms and sporozoites of both species of Plasmodium. Although the ultimate validation of this model depends upon human trials, over the past two decades these monkeys have proved very useful to test multiple malaria vaccine candidates prior to trials in humans. A good correlation between the B- and T-cell epitopes recognised by humans and by immunised monkeys has been documented, and cross reactivity between reagents for human and Aotus cytokines and lymphocyte markers have been identified and are facilitating the selection of vaccine candidates for clinical trials. Aotus also represents a good model for the screening of anti-malarial drugs and the understanding of malaria pathogenesis as well. In view of the decreasing availability of these primates, breeding programs and biomedical research facilities must be improved in countries of primate origin.     

The context of tetanus toxoid application influences the outcome of antigen-specific and self-directed humoral immune response

Results are presented concerning our attempts to create a suitable model system for studying the connection between microbial antigen (micAg), autoimmunity and autoimmune disease on the basis of hyper-immunization and application of micAg in different contexts. Our research was focused on tetanus toxoid (TTd) as a model micAg. Non-pretreated and complete Freund's adjuvant pretreated BALB/c mice were immunized with high doses of TTd mixed with glycerol or aluminum hydroxide as adjuvants. The main aims of the experiments were to evaluate the properties of induced humoral immune responses, evaluate the pathological potential of induced immune responses and determine possible correlations between the properties of a humoral immune response and its pathological potential. The production of TTd-specific and self-reactive β₂-glycoprotein I (β₂-GP I)-specific antibodies (Abs) was detected in all groups but with specific, context-related properties. Analysis of pregnancy-related pathology (anti-β₂-GP I Abs-associated) showed differences in the pathological potential of the induced immune response. It was demonstrated that severity of pathology is positively correlated to the abundance of IgG that recognizes β₂-GP I adsorbed onto phosphatidylserine, and to IgG affinity. Furthermore, it was demonstrated that molecular mimicry, which results in generation of anti-β₂-GP I Abs upon TTd immunization, is necessary but not sufficient for the development of pregnancy-related pathology.     

Computer-task testing of rhesus monkeys (Macaca mulatta) in the social milieu

Previous research has demonstrated that a behavior and performance testing paradigm, in which rhesus monkeys (Macaca mulatta) manipulate a joystick to respond to computer-generated stimuli, provides environmental enrichment and supports the psychological well-being of captive research animals. The present study was designed to determine whether computer-task activity would be affected by pair-housing animals that had previously been tested only in their single-animal home cages. No differences were observed in productivity or performance levels as a function of housing condition, even when the animals were required to “self-identify” prior to performing each trial. The data indicate that cognitive challenge and control are as preferred by the animals as social opportunities, and that, together with comfort/health considerations, each must be addressed for the assurance of psychological well-being.