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Biomedical subjects

J G Howard

Publications and source records attributed to J G Howard.

At least 91 records · Page 5Linked to original sources
PubMed1976

Mechanisms of resistance against experimental Trypanosoma cruzi infection: the importance of antibodies and antibody-forming capacity in the Biozzi high and low responder mice.

The role of antibodies and the host's antibody-forming capacity in resistance to Trypanosoma cruzi infection has been investigated in the Biozzi high and low responder lines of mice. Ab/L animals with low antibody-forming capacity were found to be more susceptible to i.p. infection with trypomastigotes than high responders (Ab/H), whereas non-selected Swiss albino mice showed an intermediate level of susceptibility. The correlation between antibody-forming potentiality and susceptibility was consistently observed with both the Y and Tulahuén strains of the parasite, which differ in their preferential tissue tropism as well as virulence. A similar divergence in susceptibility was observed after subcutaneous infection with the Y strain which produced a more fulminating disease. Although Ab/L mice neither produced a significant antibody response to the parasite nor responded to prophylactic immunization with killed T. cruzi epimastigotes, they could be effectively protected by passive transfer of immune plasma.

Animals↗
PubMed1975

Role of epitope density in the induction of immunity and tolerance with thymus-independent antigens. II. Studies with 2,4-dinitrophenyl conjugates in vivo.

The immunogenicity and tolerogenicity of 2,4-dinitrophenyl (DNP) conjugates of levan, type 3 pneumococcal polysaccharide (SIII), dextran B512 and dextran B 1299 with different levels of substitution were assessed in vivo. It was confirmed that, as in vitro, conjugates with low epitope density are solely immunogenic for Bmu cells, whereas higher density conjugates are both immunogenic and tolerogenic according to dosage. The maximal anti-DNP plaque-forming cell responses attainable varied by 2 log10 according to the carrier, being greatest with dextrans and least with SIII. The effect of the carrier on immunogenicity was not attributable to B cells responding to it, as concurrent tolerization by either free polysaccharide or the conjugate itself was without effect. Optimal immunization was succeeded by varying degrees of responsiveness ("exhaustion") which was greatest with the more immunogenic conjugates. In contrast, reduction of tolerizing dose by cyclophosphamide suppression was only a feature of more highly substituted conjugates.

Antibody Formation↗
PubMed1975

Influence of molecular structure on the tolerogenicity of bacterial dextrans. I. The alpha1--6-linked epitope of dextran B512.

Native dextran B512 is a near-linear glucose polymer with 96 per cent alpha1--6 and 4 per cent alpha1--3 linkages and a molecular weight (mol. wt) of 8 X 10(7). Sheep RBC sensitized with its O-stearoyl derivative (prepared by a modified method) have been used satisfactorily in direct PFC assays. B512 immunizes BALB/c mice optimally with doses of 1--10 mug and produces B-cell tolerance with 1 mg upwards. The specificity of the response determined by PFC inhibition analysis, is directed towards an alpha1--6-linked epitope. High dose tolerance is not preceded by immunity and is stable on cell transfer to irradiated recipients in which responsiveness becomes perceptible after 4--6 weeks. Progressive depolymerization of this polysaccharide reduces immunogenicity and tolerogenicity, both of which are extinguished when the mol. wt falls to 2 X 10(4). Optimal immunization with B512 is succeeded by partial tolerance (previously characterized by analogous levan experiments as a B-cell exhaustion process). The tolerance threshold dose of B512 is reduced 1000-fold during immunosuppression with cyclophosphamide. PFC inhibition studies supported the contention that tolerogenicity of polysaccharides is influenced by their overall binding capacities. A direct relationship between inhibitory and tolerogenic activities was found both with B512 fractions of varying mol. wt and with heterologous dextrans. The similarities between B512 and levan argue against the association of a highly branched structure with greater tolerogenicity. The effect of reducing the percentage of alpha1--6 linkages in dextrans suggests, however, that epitope density probably plays a contributory role in determining the outcome of interaction between polysaccharides and B cells.

Animals↗
PubMed1975

Influence of molecular structure on the tolerogenicity of bacterial dextrans. II. The alpha1--3-linked epitope of dextran B1355.

Dextran B1355 is a branched glucose polymer containing 57 per cent alpha1--6, 35 per cent alpha1--3 and 8 per cent alpha1--2/1--4 linkages. Direct PFC responses to B1355 can be measured with sheep RBC sensitized with its O-stearoyl or palmitoyl derivative, and, as shown by inhibition analysis, are specific for an eptiope which is dependent on alpha1--3 linkages. B1355 is a potent immunogen in BALB/c mice producing peak PFC levels which approach 10(6) per spleen following an optimal dose of 1 mg. By contrast, the alpha-1--3-linked epitope of B1355 is feebly tolerogenic, for even 10 mg still induces a strong initial response. Mice given 1--10 mg sustain PFC levels 1--2 log10 above background for several months, but do not respond further to restimulation. Full recovery is attained by their spleen cells within 1 week of transfer into irradiated recipients. Deeper tolerance to this epitope was attained in vivo only when these larger doses of B1355 were injected during cyclophosphamide suppression. Two exceptions to this weak tolerogenicty were found. First, BALB/c spleen cells developed durable partial alpha1--3 tolerance following 2-hour incubation with B1355 in vitro. Second, CBA mice were fully tolerized by doses of 1 mg upwards. It is argued from these and other data in the accompanying papers that the relative resistance of BALB/c mice to induction of alpha1--3 tolerance is explicable neither as part of a more general phenomenon based on macrophage activity nor as due to an inadequate epitope density. A possible explanation based on features of the genetically determined high alpha1--3 responsiveness of BALB/c B cells is discussed.

Animals↗
PubMed1975

Influence of molecular structure of the tolerogenicity of bacterial dextrans. III. Dissociation between tolerance and immunity to the alpha1--6- and alpha1--3-linked epitopes of dextran B1355.

Dextran B1355 induces a direct PFC response detectable with dextran B512-sensitized red cells which is directed towards an alpha1--6-linked glucose epitope. This response is distinguishable from the alpha1--3-linked specificity assayed by homologous sensitization in that: (a) it is totally suppressed in donors previously rendered tolerant of B512; (b) the PFC are sensitive to inhibition by B512 and isomaltohexaose. The alpha1--6 epitope of B1355 is less immunogenic in BALB/c mice than that with alpha1--3 linkage, inducing a lower amplitude of response and requiring a 100-fold greater minimal dose, while conversely, it is the more effective tolerogen. No alpha1--6-specific response develops in 50 per cent of mice given 10 mg of B1355 and all become totally unresponsive within 14 days. This tolerant state remains stable when spleen cells are transferred to irradiated recipients. By comparison, parallel depression of the alpha1--3 response is not great and rapidly lost by similar transfer. No correlation was observed between the levels of alpha1--6 suppression and alpha1--3 response induced by 10 mg of B1355 in individual mice. The dissociative aspects of the responses to these two epitopes present on the same molecule are discussed in relation to some current theories of B-cell tolerance induction. It is argued that the present findings are contrary to those models which attribute a causal role to mitogenic overstimulation or failure to generate an extrinsic 'second signal'.

Animals↗