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Biomedical subjects

J F Albright

Publications and source records attributed to J F Albright.

At least 19 recordsLinked to original sources
PubMed2000

Soluble receptors and other substances that regulate proinflammatory cytokines in young and aging humans.

Relatively little is known about changes in soluble receptors and other agonists/antagonists that may regulate cytokine actions in aging humans. We have studied age-associated changes in human subjects of (a) the plasma levels of interleukin-1 soluble receptor (IL-1sRII), interleukin-1 receptor antagonist (IL-1ra), tumor necrosis factor soluble receptor-II(75kDa; TNFsRII), and interleukin-6 soluble receptor (IL-6sR) and (b) the ability of their blood mononuclear cells to produce those soluble factors spontaneously and after phytohemagglutinin (PHA) stimulation. Aging subjects (50-67 years) had significantly higher plasma levels of IL-1ra, significantly lower levels of TNFsRII and IL-6sR than young subjects (25-35 years), and no significant change in the level of IL-1sRIL There was less spontaneous output of IL-1ra and TNFsRII by peripheral blood mononuclear cells (PBMC) of aging than of young subjects, but equivalent output of both factors in response to PHA stimulation. Thus, the basal (homeostatic) output of those two factors declined with age, but the potential of the PBMC to produce the factors on stimulation did not. PHA stimulation of PBMC of either age group significantly inhibited the output of IL-6sR. These differences between the young adult and aging subjects, along with reported changes in the corresponding cytokines, presumably foreshadow changes that become more marked with further aging Therefore, immunological processes that depend on, or are modulated by, proinflammatory cytokines may differ between young and aged subjects as a consequence of the availability of regulatory soluble receptors and related agonists or antagonists. The results of this study highlight the need for further studies of the roles played by soluble receptors, and similar agonists/antagonists, in the immune responses of aged adults.

Adult↗
PubMed1999

Trypanosoma musculi: tracking parasites and circulating lymphoid cells in host mice.

Two aspects of host-parasite relationships that seem worthy of more attention are: (a) the distribution of parasites among host organs in the early course of infection, and (b) the dynamics of host lymphocyte tissue localization and recirculation during the course of infection. We have employed the derivatized aminostyrylpyridinium dye, [125I] I 2P-Di-6-ASP, to provide a relatively stable tag on both a parasite, Trypanosoma musculi, and on host mouse splenocytes, enriched B and T lymphocytes, and natural killer cells. The organ distribution of the parasites, splenocytes, and lymphocytes in recipient, host mice was tracked. Radiolabeled T. musculi localized primarily in the liver with lesser numbers in spleen, lungs, and kidneys. Per unit wet weight, the spleen accumulated parasites most efficiently. When T. musculi were inoculated intraperitoneally, most of them remained in the peritoneal space and the numbers that gained access to liver, lungs, and spleen were significantly smaller than in mice inoculated intravenously. The acquisition of parasites by the spleen (and lungs) of mice with an existing T. musculi infection was markedly inhibited. This was true also of syngeneic splenocytes and lymphocytes. In addition, lymphocytes from infected mice were significantly less likely to take residence in the spleens of normal recipient mice and were especially unlikely to localize in the spleens of infected recipients. These and other findings suggested that the inability of circulating lymphocytes to gain access to lymphoid tissues in infected mice, coupled with the poor ability of those tissues to sequester parasite antigens, could account for the known prolonged delay in the development of curative antibody response characteristic of T. musculi-infected mice. It is likely that the marked disruption of lymphoid tissue histoarchitecture that is typical of T. musculi infection contributes significantly to the failure of the tissues to sequester parasites and lymphocytes. Because lymphoid tissue disruption is seen in many parasitic infections, the findings reported here may have fairly broad relevance. In any case, the procedure described here for labeling parasites and lymphocytes should be of general utility for tracking their disposition in vivo.

Aminopyridines↗
PubMed1998

Effects of aging on the dynamics of lymphocyte organ distribution in mice: use of a radioiodinated cell membrane probe.

We have employed a derivatized aminostyrylpyridinium dye, [125I]I2P-Di-6-ASP, to provide a relatively stable tag on mixed mouse splenocytes and purified B and T cells for the purpose of tracking the distribution of those cells among the organs of normal young (4 months) and aged (> 26 months) recipient mice. Cells from both young and aged donor spleens were studied. Special emphasis was placed on localization of donor cells in the spleens of the recipients because the majority of circulating lymphocytes localize in the spleen and the spleen is the principal organ of primary immune response. There was a profound difference in the efficiency of splenic acquisition of donor cells between young and aged recipients, a difference not found in the liver, lungs, kidneys or heart. In contrast young and old donor lymphocytes lodged equally well in the spleens of recipients of the same age. It was clear that the competence of the splenic microenvironment to serve as a lodging site for circulating lymphocytes deteriorated with age. Such a change could contribute significantly to the deficient immune response of aged subjects. We suggest that aging results in significant change in the splenic extracellular matrix to serve as an adhesive substratum for lymphocytes. Our data point to a need for detailed studies on age-related changes in components of the extracellular matrix within lymphoid tissues. The novel compound which we employed for cell labeling is both radioactive and fluorescent and should be quite suitable for such studies.

Aging↗
PubMed1997

Innate control of the early course of infection in mice inoculated with Trypanosoma musculi.

Infections of mice with Trypanosoma musculi result in marked suppression of acquired humoral immunity but rapid activation of splenic NK cell cytotoxicity. We show that both NK cells and activated peritoneal space (PS) macrophages (MP) participate in the innate immune control of T. musculi infections preceding escape of curative antibody production from suppression. Splenic NK cytotoxicity reaches a peak on Days 3-4 of infection and then rapidly declines. Rising cytotoxicity is paralleled by a rising number of NK cells. The decline in cytotoxicity occurs even though the number of splenic NK cells continues to rise. The critical role of NK cells in the control of the early course of T. musculi infection was demonstrated by the effects of either depleting NK cells (antiasialo GM1 treatment) or maintaining them in an activated state (poly(I:C) injections). The importance of MP in controlling the infection was suggested by studies involving proteose peptone elicited MP both in vivo and in culture. The results presented here strongly suggest that innate immunity involving NK cells and MP can control, but not cure, T. musculi infections. Whether this early innate response influences the subsequent acquired, curative response remains to be studied. Detailed analyses of innate immunity in this experimental infection should suggest new approaches to intervention in early pathogenic infections.

Animals↗
PubMed1996

Airborne pollutants and the immune system.

The effects of airborne pollutants on the immune system have been most widely studied in the respiratory tract. Entry may occur as a volatile gas (ozone, benzene), as liquid droplets (sulfuric acid, nitrogen dioxide), or as particulate matter (diesel exhaust, aromatic hydrocarbons). The subsequent interaction with the immune system may result in local and systemic responses, and studies have shown examples of disease occurring from both overactive immune responses and immunosuppression. For the most part, airborne pollutants (small molecular weight chemicals) have to be coupled with other substances (proteins or conjugates) before they can be recognized by the immune system and exert their effects. Fortunately, this encounter rarely causes immunologically mediated human disorders. The following briefly reviews some of the disorders that may occur. Immunologically nonspecific inflammation of the lung can occur after inhalation of ozone in anyone given sufficient dose and time of exposure. Immunologically specific cell-mediated (T lymphocyte) reactions appear to predominate in chronic beryllium disease, which results in a granulomatous form of lung disease. Beryllium alone does not appear to be antigenic but requires chemical linkage with a larger molecule. Mercury-induced autoimmune disease (immune system attacks self-antigens) affecting kidneys and lungs has been demonstrated in animal models (changes similar to those seen in people with Goodpasture's syndrome). Immunosuppression can be demonstrated after exposure to polycyclic aromatic hydrocarbons (2,3,7,8-tetrachlorodibenzo-p-dioxin). Hypersensitivity (or allergic) reactions can occur after exposure to toluene diisocyanate (occupational asthma). In summary, airborne pollutants may cause a wide spectrum of immunologically mediated disorders. There is clearly an underlying genetic basis for the susceptibility to immunologic disease resulting from exposure to pollutants, but knowledge in this area is rudimentary at present. Studies have been impeded by lack of appropriate in vitro models, as well as difficulties in identifying the biologically active substance.

Air Pollutants↗
PubMed1995

Transcriptional control of IL-2 and IL-4 in T cells of young and old mice.

CD4+ T cells of aged compared to young subjects are defective in their responses to antigens and soluble mitogens. We asked whether or not there is a defect in the translocation of transcription factors (TF) in CD4+ T cells of aged mice. Electrophoretic mobility shift assays of three TF that regulate IL-2 gene expression, viz., Oct1/2, NF kappa B, and AP-1, in nuclear extracts of cells stimulated with immobilized anti-CD3 epsilon revealed no significant difference between cells of young and old mice. The nuclear levels of all three TF were lower in cells of both young and aged mice that were stimulated with Con A and lower in aged than in young. Similar assays of consensus sequences 1 and 2 (CS1 and CS2) TF involved in IL-4 gene transcription in cells of the Th2 subset revealed significant translocation of CS1 following stimulation of both young and aged cells with anti-CD3, more in cells of young than in those of aged mice. In contrast, the most evident effect of Con A stimulation was the accumulation of CS2 in nuclei of cells of aged mice. Apparently, there is no detrimental effect of senescence on the basic mechanisms of translocation of TF. The differences between stimulation with immobilized anti-CD3 epsilon and Con A can be explained by the relative abundance of memory-like CD4+ T cells which accumulate with age (and are defective in Ca2+ mobilization and signaling) and by the poor ability of memory-like cells in the aged to respond to CD28 costimulation.

Age Factors↗
PubMed1994

Antibody-facilitated macrophage killing of Trypanosoma musculi is an extracellular process as studied in several variations of an in vitro analytical system.

Antibody-facilitated macrophage (MP) destruction of Trypanosoma musculi involves ingestion and intracellular degradation of the parasites. It is likely, however, as we show here, that death of the trypanosomes is extracellular and it is the corpses that are ingested by MPs. We have utilized both peritoneal MPs and a cloned line (WLG 5) of mouse MPs to analyze the killing of T. musculi. Both types of MP were more effective when activated by interferon-gamma (IFN-gamma) rather than lipopolysaccharide (LPS). When activated by both, LPS diminished the killing activity stimulated by IFN-gamma, perhaps by changing the spectrum of lysins/toxins released by the MPs. Nitric oxide (NO) was found to be toxic for T. musculi and to be responsible, in part, for MP killing of the parasites. Although antibody and complement in concert caused lysis of T musculi, complement was not required for MP killing of the parasites. In the course of this investigation, we developed an in vitro system, involving line 5 MPs and plasma from infected mice containing resident parasites, that should prove satisfactory for detailed analyses of the mechanisms of the antibody-dependent, cell-mediated cure of T. musculi infection.

Animals↗
PubMed1994

Ageing alters the competence of the immune system to control parasitic infection.

The elderly are more susceptible to infections with various pathogenic organisms that are young-adults or middle-aged individuals. Certain microorganisms that are non-pathogenic in adults may cause serious infections in the elderly. This heightened susceptibility of the elderly is most likely a reflection of the age-associated decline in the competence of the immune system. It appears that the population of T cells is altered with advanced age and, possibly, the efficiency of the monocyte/macrophage cells to destroy microbial invaders declines. There is a small, but compelling, body of literature which shows that the elderly are particularly susceptible to protozoan and metazoan parasites. We have studied the markedly increased severity of infections in aged mice with the mouse-specific Trypanosoma musculi; both the parasite burden and the duration of infection are substantially greater in old compared to young mice. It appears that this difference is due, to a large extent, to the relatively weak ability of aged animals to generate cytokines associated with the TH1 subset of CD4+ T cells; in particular, the weak ability to generate IL-2 and IFN gamma which are involved in the selective expression of curative, parasite-specific antibody of the IgG2a isotype. A striking difference between young and aged mice is in the response of IL-3 producing cells to the parasite infection; IL-3-producers decline during infection in young mice but increase markedly in aged animals. There are several advantages to using T. musculi as a prototype pathogen for studying age-related susceptibility to infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1994

Changes in the subsets of CD4+ T cells in Trypanosoma musculi infection: delay of immunological cure in young mice and the weak ability of aged mice to control the infection.

After a 3 week course (approximately), during which there is marked lymphoid hyperplasia, Trypanosoma musculi infections in young-adult mice are cured by an immune mechanism involving antibodies of the IgG2a isotype. Both the lymphoid hyperplasia and IgG2a antibody response are T-cell-dependent events and both processes appear to be defective in aged mice. The purpose of the studies reported here was to elucidate the effects of T. musculi infection on subsets of T cells for two reasons: (i) to gain insight into the probable roles of selected cytokines (IL-2, IL-4 and IFN-gamma) in facilitating the production of curative, IgG2a antibodies, and (ii) to examine the hypothesis that aging affects the competence of CD4+ T cells to participate in immunological control of infections. The major conclusions from these studies are that: (i) T. musculi infection of mice induces rapid change in the CD4+ T cell population toward predominance of the activated or memory (CD45RBloCD44hi) phenotype, cells which produce IFN-gamma, II-3, IL-4 and IL-5, accompanied by profound inhibition of IL-2 production, and (ii) in the old mice these changes are superimposed on the natural age-associated changes in the same direction (i.e. toward predominance of CD45RBloCD44hi T cells). Thus, in the old animals, the combined changes of aging and infection, moving in the same direction, are devastating, resulting in the aged animals being unable, or barely able, to control infection.

Aging↗
PubMed1992

Contemporary topics in immunology: approaches to immunotherapy emerging from basic research.

The seventh symposium in the series "Contemporary Topics in Immunology" was held on April 21, 1991, at the FASEB meeting in Atlanta, Georgia. It was sponsored by the National Institute of Allergy and Infectious Diseases, The American Association of Immunologists, and the Clinical Immunology Society. Five topics were discussed by leading researchers in areas of immunology that currently are of exceptional interest and show promise of leading to new advances in the prevention and treatment of human diseases. The topics included: the interactions between immunogenic peptides, class I MHC molecules and T cell receptors; initiation, maintenance, and breakdown of self-tolerance in B lymphocytes; inflammatory disease in HLA-B27 transgenic rats; properties and functions of interleukin-10; and transforming growth factor-beta in reproductive immunology. The exceptional quality of the presentations in this seventh symposium exemplified perfectly the path of basic research that often leads from the laboratory to the clinic.

Animals↗
PubMed1991

Contributions of basic immunology to human health.

The sixth symposium in the series "Contemporary Topics in Immunology" was held in New Orleans on June 3, 1990, at the joint meeting of The American Association of Immunologists and the American Society of Biochemistry and Molecular Biology. The symposium was sponsored jointly by The American Association of Immunologists, the Clinical Immunology Society, and and the National Institute of Allergy and Infectious Diseases, and was titled "The Contributions of Basic Immunology to Human Health." Five speakers, whose research has clear relevance to the treatment and prevention of major human diseases, discussed topics of great current interest: hematopoietic stem cells, cell adhesion and lymphocyte homing; the complexities of autoimmunity and approaches to diverting or depressing autoaggressive immunity; structure and functions of the interferons and the construction of designer and chimeric interferons; the varied functions of transforming growth factors and molecular events that regulate the synthesis of TGF beta; and the roles of cytokines in the expression of human immunodeficiency virus and the prospects for controlling HIV infections by regulating selected cytokines. This symposium will be remembered for the exceptional clarity with which each speaker illustrated how fundamental knowledge in immunology fuels advances in the treatment and prevention of those human disorders that involve the immune system.

Autoimmunity↗
PubMed1991

Rodent trypanosomes: their conflict with the immune system of the host.

Rodent trypanosome infections provide the opportunity to study major phenomena that are displayed in many parasite-host combinations and, therefore, the chance to contribute to the elucidation of those phenomena. Here, Julia and Joseph Albright focus on the immune responses to rodent trypanosomes and on the tricks the parasites play to minimize the effects of those responses.

Journal Article↗
PubMed1990

Fluctuations in subsets of splenocytes and isotypes of Ig in young adult and aged mice resulting from Trypanosoma musculi infections.

A prominent feature of parasitic infections is the marked hyperplasia of lymphoid tissues. The resultant disruption of those tissues may be a major cause of the immunodepression that typifies parasitic infections. Trypanosoma musculi infections in mice evoke lymphoid hyperplasia and depressed immune responses. T. musculi infections are more severe in C3H than in C57BL/6 (B6) mice; and more severe in aged mice of either strain, compared with young adults. This report concerns a flow cytometric analysis of splenic leukocytes, identified by various surface Ag, in young and aged, trypanosome-infected mice of C3H and B6 strains. Companion studies included quantification of serum Ig isotypes at intervals during infection. The results support the following conclusions: a) all major types of splenic leukocytes were activated by trypanosome infection resulting in enlargement of the cells and proliferation ("blastogenic response"); b) in all young-adult mice and in aged B6 mice (but not aged C3H mice) Thy-1+, Ly-1+, and Ly-4+ cells increased moderately during infection whereas the number of Ly-2+ cells remained constant; c) all cells of the B lineage increased during the course of infection (except in aged C3H mice) with disproportionate increases in the most mature stage (IgG+); d) the responses of young adult C3H and B6 mice to infection differed as illustrated by the ability of B6, but not C3H, mice to limit hyperplasia and reverse the effect; e) aging of B6 mice was reflected by relative inability to regulate generation of mature Ig-producing cells; f) aging of C3H mice was severe as reflected by the relative inability of most subsets of leukocytes to react to the infection, possibly because of abnormalities that were intrinsic in aged, normal C3H mice. It is likely that: a) disruption of lymphoid tissue, probably mediated by alterations in the production of and responsiveness to cytokines, is responsible for the depressed ability of the immune system to defend against parasites; and b) such disruptive effects, being more pronounced in aged animals and less easily brought under control, account for the greater vulnerability of aged animals to parasitic infection.

Aging↗
PubMed1990

Immune and nonimmune regulation of the population of Trypanosoma musculi in infected host mice.

A clear understanding of the population dynamics of trypanosome infections is lacking. In the case of murine Trypanosoma musculi infections, there are no answers to questions concerning (i) the nature of the prolonged plateau phase during which the number of parasites present in the host remains nearly constant (is it a static or dynamic steady state?); (ii) the origin of new parasites, if the plateau is a dynamic steady state, given the relatively early disappearance of generative forms from the bloodstream; and (iii) the role, if any, of a putative ablastin (reproduction-restricting antibody) in regulating the population dynamics of T. musculi infections. We describe here the results of studies of the number and distribution of mature and reproductive forms (RF) in the blood and peritoneal space of both immunocompetent and cyclophosphamide-treated mice throughout the course of infection. While the RF disappeared from the blood within a few days after parasite inoculation, a high fraction (20 to 30%) of the parasites in the peritoneal space were RF throughout the course of infection and, thus, represented a source of new parasites. If an ablastin is responsible for inhibiting RF in the blood, it appeared to have no effect on RF in the peritoneal space. The results of this investigation support the conclusion that the control of the dynamics of T. musculi infections is largely nonimmunological (until cure of the infection) and probably is exercised by the supply of nutrients and reproduction-inhibiting (nonimmunological) and maturation-promoting factors that affect the generative fraction of the population.

Animals↗
PubMed1990

The liver as a major site of immunological elimination of murine trypanosome infection, demonstrated with the liver perfusion model.

The isolated liver perfusion model has been used to investigate immunological elimination of bacteria and yeasts but not for analysis of mechanisms of immunological destruction of extracellular parasitic protozoa. Extracellular trypanosomes are eliminated primarily through antibody (and complement?)-promoted hepatic (Kupffer cell) uptake and destruction. We studied the suitability of the isolated liver model system for analyzing the mechanism of immune elimination of mouse-specific Trypanosoma musculi and identified several factors which can complicate such analyses: (i) mechanical trapping of trypanosomes that are quite large (for example, reproducing forms or epimastigotes) or are nonviable and, therefore, nondeformable; (ii) variable species and concentrations of cytadhesive molecules; and (iii) the integrity and composition of the trypanosomal surface coat. There was a substantial difference between hepatic retention of infused T. musculi organisms coated with a specific antibody and those devoid of antibody when both were suspended in normal mouse serum. The difference appeared sufficient to allow accurate quantitative studies of immune destruction in the liver. Studies of whole mice indicated that quantitative investigations of immunological elimination of trypanosomes from the bloodstream are likely to be complicated by problems such as cytadherence of parasites to host endothelial cells and mechanical trapping. Uptake by the liver and spleen appeared more reliable. Thus, the isolated liver perfusion model should significantly benefit studies to elucidate the mechanisms of immune elimination of extracellular trypanosomes.

Animals↗