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Biomedical subjects

J H Humphrey

Publications and source records attributed to J H Humphrey.

At least 19 recordsLinked to original sources
PubMed1992

Vitamin A deficiency and attributable mortality among under-5-year-olds.

Reported are estimates of the prevalence in developing countries of physiologically significant vitamin A deficiency and the number of attributable deaths. The WHO classification of countries by the severity and extent of xerophthalmia was used to categorize developing countries by likely risk of subclinical vitamin A deficiency. Using vital statistics compiled by UNICEF, we derived population figures and mortality rates for under-5-year-olds. The findings of vitamin A supplementation trials were applied to populations at-risk of endemic vitamin A deficiency to estimate the potential impact of improved vitamin A nutriture in reducing mortality during preschool years. Worldwide, over 124 million children are estimated to be vitamin A deficient. Improved vitamin A nutriture would be expected to prevent approximately 1-2 million deaths annually among children aged 1-4 years. An additional 0.25-0.5 million deaths may be averted if improved vitamin A nutriture can be achieved during the latter half of infancy. Improved vitamin A nutriture alone could prevent 1.3-2.5 million of the nearly 8 million late infancy and preschool-age child deaths that occur each year in the highest-risk developing countries.

Age Factors↗
PubMed1986

Regulation of in vivo immune responses: few principles and much ignorance.

An attempt is made, based largely on reports of experiments carried out in vitro, to piece together the sequence of events between the interaction of antigens with B or T lymphocytes and the immune responses which result. These include stimulation of B lymphocytes to secrete antibody or to become B memory cells, and stimulation of T helper cells and cytotoxic/suppressor T cells to multiply and become functional effector cells. Thymus-independent (T1) stimulation is described of a subpopulation of B cells by poorly degradable immunogens with multiple epitopes, and the generation of B memory cells, as well as stimulation of B cells requiring cooperation with T cells. Stimulation of T helper (TH) cells by antigens involves first activation by interleukin 1 (IL-1) and then presentation of the antigen at the surface of antigen-presenting cells (usually macrophages, dendritic cells or B cells) in association with class II major histocompatibility complex molecules (MHC II); for extrinsic (foreign) proteins this requires initial capture of the protein, followed by denaturation and/or degradation so as to associate the molecule or fragments with MHC II. Some peptides can become suitably associated without further degradation, whereas T1 antigens may be unable to become associated effectively. T cells so stimulated express receptors for interleukin 2 (IL-2), and secrete various molecules, including factors which stimulate B cells to divide and/or secrete Ig, interferon-gamma and IL-2. In turn, IL-2 causes proliferation of TH and cytotoxic/suppressor T cells. Interferon-gamma stimulates the expression of MHC II by macrophages and some epithelial cells and increases the activity of NK (natural killer) cells. This simplified account embraces many of the experimental observations, but there are sufficient exceptions to make clear that much remains to be discovered even in respect of the interactions of antigen-presenting cells, T cells and B cells in vitro. Application of such general principles to predict the outcome of immunization in vivo would need also to take into account the microenvironments in lymphoid tissues where antigens are retained, and the flow of lymphocytes through them; how long the antigens persist; and how the immune response is modified by responses already elicited, including the idiotype network. Because such information is not usually available, enlightened guess-work may still be the best guide to practice.

Animals↗
PubMed1986

Human immune responses in vivo to protein (KLH) and polysaccharide (DNP-Ficoll) neoantigens: normal subjects compared with bone marrow transplant patients on cyclosporine.

Thymus-independent (TI) and thymus-dependent (TD) primary immune responses were measured in 67 controls and 13 bone marrow transplant (BMT) recipients treated with cyclosporine (CSP) by immunizing with a synthetic antigen (DNP-Ficoll) and keyhole limpet haemocyanin (KLH). DNP-Ficoll induced similar TI antibody responses in controls and BMT recipients except that antibody levels declined much more rapidly in BMT recipients. The IgM and IgG antibodies induced by DNP-Ficoll only recognized the DNP epitope and not the Ficoll carrier. Both IgM and IgG classes of antibody showed similar TI behaviour upon immunization and re-immunization. The antibodies to DNP-Ficoll were overwhelmingly of the IgG1 subclass. The TD response to KLH evoked both delayed hypersensitivity (DH) and antibody production. DH developed at the site of immunization in 68% of controls and in 88% upon subsequent challenge with KLH. None of the BMT recipients on CSP developed DH. KLH antibody arose in 88% of controls but in only one BMT recipient on CSP. Eight BMT recipients were re-immunized with KLH 2-6 weeks after stopping CSP and only one made primary DH and antibody responses, arguing that CSP inhibited priming as well as any detectable response to KLH. The immunization procedure described has proved a sensitive and comprehensive method of quantitating human immune responses in vivo and is readily adaptable for in vitro studies.

Adolescent↗
PubMed1986

Inhibition of growth of Listeria monocytogenes in vitro, by immunologically activated mouse resident macrophages.

Resident peritoneal macrophages, spleen macrophages and Kupffer cells isolated from normal CBA mice were treated with supernatants from spleen cells of normal or immunized mice, and cultured in the presence of heat-killed Listeria monocytogenes. The capacity of the macrophages, infected in vitro, to control the growth of Listeria was tested. In macrophages treated with supernatant from normal spleen cells, the organisms multiplied extensively during 24 h but in those treated with supernatant from immune spleen cells, growth was greatly inhibited. Macrophages isolated from mice irradiated with 8-9.5 Gy and treated with immune spleen cell supernatant, were as efficient or even more than those from unirradiated mice. The use of multispot slides proved to be a convenient and economical means of culturing and examining cells.

Animals↗
PubMed1985

Splenic dependence of the antibody response to thymus-independent (TI-2) antigens.

The murine antibody response to T-independent (TI)-2 antigens [2,4-dinitrophenyl-Lys-Ficoll (DNP-FIC) and DNP-hydroxyethyl starch (HES)] was impaired long after splenectomy, while responses to TI-1 [trinitrophenylated lipopolysaccharide (TNP-LPS)] and thymus-dependent [TNP-keyhole limpet hemocyanin (KLH)] antigens were largely unaffected. The antibody response to these TI-2 antigens was exclusively against the conjugated epitopes [DNP-, fluorescein isothiocyanate (FITC)- or tetramethylrhodamine isothiocyanate (TRITC)-Ficoll or -HES]. Fluorescent conjugates of Ficoll and HES localize selectively to the splenic marginal zone macrophages. This localization was not affected by 750 cGy of X-irradiation, but the antibody response to the TI-2 antigens was abrogated for 14 days. Administration of spleen cells restored the antibody response to these TI-2 antigens in otherwise intact irradiated mice but not if they had been splenectomized. Our findings indicate that the antibody response to TI-2 antigens depends upon stimulation of B cells in a splenic environment. This probably involves antigen presentation by marginal zone macrophages.

Animals↗
PubMed1985

The function and origin of follicular dendritic cells.

Follicular dendritic cells (dendritic reticular cells) in germinal centres bind antigen-antibody complexes via C3 receptors and retain the complexes at their surface for long periods of time. The follicular dendritic cells (FDC) are distinct from macrophages and from dendritic cells found in T-dependent areas, and are not derived from bone marrow stem cells. On histological evidence it has been proposed that they are derived from reticulum cells. Complexes are probably transported to FDC by a subpopulation of B cells in the marginal zone. Binding of complexes to FDC causes germinal centre enlargement and is a very efficient, and possibly essential stimulus to the generation of B memory cells which recognize epitopes on antigen or antibody in the complexes. An hypothesis is discussed which draws together these observations and suggests that antigen on FDC plays a central role in control of humoral immunity.

Animals↗
PubMed1985

Splenic macrophages: antigen presenting cells for T1-2 antigens.

Thymus-independent antigens type 2 (T1-2) such as DNP-Ficoll or DNP-hydroxyethyl starch are selectively retained in mice and rats by a distinct population of macrophages in the marginal zone of the white pulp of the spleen and in the marginal sinus and septa and medulla of lymph nodes. There is suggestive evidence that the antibody response to the haptenic determinants, which is rapid in onset and persists for many weeks, is largely made by a sessile subpopulation of B cells in the spleen marginal zone characterized by the presence of surface IgM but lacking IgD. Splenectomy in adult mice, rats and humans greatly diminishes and delays the antibody response to DNP-Ficoll, but has no such effect on the response to thymus-dependent, or (in mice) to T1-1 immunogens. In humans, if DNP-Ficoll had been administered prior to splenectomy, a normal antibody response was made when the antigen was readministered after splenectomy, indicating that once the responding B cells had been stimulated they were no longer confined to the spleen. Experiments in mice showed that after elimination of B cells by irradiation, responsiveness to T1-2 antigens could be restored by spleen cells isolated as single-cell suspensions provided that the architecture of the spleen remained, but could not be restored if the mice had been splenectomized. This implies that both the spleen B cells and the marginal zone macrophages are required.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1977

The generation of memory cells. I. The role of C3 in the generation of B memory cells.

Adult thymectomized, repopulated mice were chronically depleted of circulating C3 by treatment with cobra venom factor after primary immunization with dinitrophenylated haemocyanin (DNP-KLH). This treatment totally abrogated the development of B-cell memory in such mice, as assayed by a co-operative lymphocyte transfer. The failure of memory development appeared to involve impaired precursor proliferation following priming. It was further shown that the localization of DNP-KLH in splenic lymphoid follicles is both antibody and C3-dependent; thymus-deprived mice make sufficient antibody to DNP-KLH to effect follicular localization of the antigen. On the basis of these and earlier observations we suggest that the development of B-memory cells involves the formation of antigen-antibody-C3 complexes on dendritic cells in lymphoid follicles. C3 may serve to stabilize the antigen bridge between dendritic cells and virgin precursors. In complete contrast, C3 depletion had little effect on the functional expression of primed B cells, thus suggesting that only the early stages of B-cell triggering are C3 dependent.

Animals↗
PubMed1976

B cell tolerance induced by polymeric antigens. I. Comparison of the dose and epitope density requirements for inactivation of primed and unprimed B cells in vivo.

Hapten [2,4-dinitrophenyl (DNP)]-specific tolerance was induced in nonimmune or DNP-hemocyanin (DNP-KLH) primed mice by administering hapten-conjugated type 3 pneumococcal polysaccharide (DNP-lys-S3). The dose of DNP-lys2.5-S3 required to suppress the primary anti-DNP antibody responses was approximately ten times higher than that required to suppress the secondary response. Large doses of lightly substituted antigen (DNP-lys0.6-S3) had no effect on primary antibody responses, while small doses of this conjugate suppressed 90-95% of the secondary response. The conclusion from this (presumably B cell) tolerance model is that B lymphocytes "mature" in their susceptibility to tolerization following primary contact with immunogen, since primed cells are inactivated by lower doses of tolerogen, and by tolerogen with lower epitope density, than nonimmune B cells. These and other data suggest that the tolerance threshold of B lymphocytes is related to their state of differentiation, and especially to their antigen-binding characteristics.

Animals↗