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R J Hodes

Publications and source records attributed to R J Hodes.

At least 37 records · Page 2Linked to original sources
PubMed1997

Tales of tails: regulation of telomere length and telomerase activity during lymphocyte development, differentiation, activation, and aging.

Telomerase activity and the regulation of telomere length are factors which have been implicated in the control of cellular replication. These variables have been examined during human lymphocyte development, differentiation, activation, and aging. It was found that telomere length of peripheral blood CD4+ T cells decreases with age as well as with differentiation from naive to memory cells in vivo, and decreases with cell division in vitro. These results provide evidence that telomere length correlates with lymphocyte replicative history and residual replicative potential. In contrast, telomere length appears to increase during tonsil B-cell differentiation and germinal center (GC) formation in vivo. It was also found that telomerase activity is highly regulated during T-cell development and B-cell differentiation in vivo, with high levels of telomerase activity expressed in thymocytes and GC B cells, and low levels of telomerase activity in resting mature peripheral blood lymphocytes. Finally, resting lymphocytes retain the ability to upregulate telomerase activity upon activation, and this capacity does not appear to decline with age. Although the precise role of telomerase in lymphocyte function remains to be elucidated, telomerase may contribute to protection from telomere shortening in T and B lymphocytes, and may thus play a critical role in lymphocyte development, differentiation and activation. The future study of telomerase and its regulation of telomere length may enhance our understanding of how the replicative lifespan is regulated in lymphocytes.

Animals↗
PubMed1996

Regulated expression of telomerase activity in human T lymphocyte development and activation.

Telomerase, a ribonucleoprotein that is capable of synthesizing telomeric repeats, is expressed in germline and malignant cells, and is absent in most normal human somatic cells. The selective expression of telomerase has thus been proposed to be a basis for the immortality of the germline and of malignant cells. In the present study, telomerase activity was analyzed in normal human T lymphocytes. It was found that telomerase is expressed at a high level in thymocyte subpopulations, at an intermediate level in tonsil T lymphocytes, and at a low to undetectable level in peripheral blood T lymphocytes. Moreover, telomerase activity is highly inducible in peripheral T lymphocytes by activation through CD3 with or without CD28 costimulation, or by stimulation with phorbol myristate acetate (PMA)/ionomycin. The induction of telomerase by anti-CD3 plus anti-CD28 (anti-CD3/CD28) stimulation required RNA and protein synthesis, and was blocked by herbimycin A, an inhibitor of S pi protein tyrosine kinases. The immunosuppressive drug cyclosporin A selectively inhibited telomerase induction by PMA/ionomycin and by anti-CD3, but not by anti-CD3/CD28. Although telomerase activity in peripheral T lymphocytes was activation dependent and correlated with cell proliferation, it was not cell cycle phase restricted. These results indicate that the expression of telomerase in normal human T lymphocytes is both developmentally regulated and activation induced. Telomerase may thus play a permissive role in T cell development and in determining the capacity of lymphoid cells for cell division and clonal expansion.

Antigens, CD↗
PubMed1996

The role of CD28 costimulation in immune-mediated responses against mouse mammary tumor viruses.

Infectious mouse mammary tumor viruses (MMTV) encode superantigens (SAg) which, when presented in association with permissive class II MHC molecules, are recognized by those T cells that express appropriate TCRs. Recent findings have indicated that expression of a permissive MHC class II product and of a specific TCR are also critical to susceptibility of newborn mice to infection with milk-borne MMTV, suggesting that SAg-mediated T cell activation may play a facilitating role in viral infection. Because effective Ag-specific T cell activation can require costimulatory signals in addition to TCR-mediated recognition, the role of the CD28 costimulatory receptor was analyzed in responses of neonatal and adult mice to MMTV challenge. Mice that were deficient in CD28 expression as a result of gene targeting were compared with CD28-intact littermates. In response to parenteral challenge with MMTV, CD28-deficient adult mice exhibited reduced expansion of MMTV SAg-reactive T cells in draining LNs, decreased cytokine production, and decreased B cell activation and Ig secretion. These results indicate that optimal T and B cell responses to MMTV challenge, as reflected in the parameters measured, are CD28 dependent. In contrast, CD28 absence did not impair TCR-V beta-specific clonal deletion induced by neonatal exposure to MMTV. Further, analysis of susceptibility to viral infection in neonatally exposed mice revealed that CD28 deficiency did not interfere with SAg-dependent MMTV infection. Failure to identify CD28 dependence of MMTV infection suggests either the absence of a costimulatory requirement in the events that lead to viral infection or a redundancy in costimulatory signals that support infection.

Animals↗
PubMed1996

The National Institute on Aging at its twentieth anniversary: achievements and promise of research on aging.

As these distinguished speakers demonstrate, the research community should take enormous pride in its many achievements to date, as well as in the scientific break-throughs that appear to be just on the horizon. However, existing gaps in our knowledge about the aging process certainly will require a great deal more of our attention. As former NIA director Robert N. Butler, MD, cautioned in the symposium's opening panel, "We remain ill-prepared for the 21st Century when population aging will become unprecedented. We already feel the impact of a revolution in longevity that has added 28 years to the life expectancy of Americans since the beginning the century. But we are not prepared for the baby boomers--the largest generation in U.S. history and one-third of our present population, the first of whom will turn 65 in 2011. "I regard the baby boomers as a generation at risk. We still devote relatively few resources to understanding the biology of aging. Although we have made progress in understanding the pathogenesis of Alzheimer's disease, we are a long way from a cure. While we have some insights into the demography of aging, the social impact of population aging upon society and, in turn, the psychosocial experiences of growing older, we are a long way from understanding the full implications of any of these." Maintaining and improving the health and well-being of older people will be among the greatest social challenges of the next century. Research into aging and the diseases common to older people undoubtedly holds the key to addressing the health and social needs of older people and reducing the risk factors driving the increased and costly need for long-term care. At the same time, the effects of downsizing and cost constraints in all segments of today's society challenge our ability to address these needs. Although scientists today face serious challenges to completing the work that research already has generated and to initiating new projects, we are energized by the potential for widespread benefit. Using that energy, in 20 years' time we should expect to look back with the same sense of accomplishment and ahead with the same enthusiasm for achievements yet to come.

Black or African American↗
PubMed1995

Inhibition of transplant rejection following treatment with anti-B7-2 and anti-B7-1 antibodies.

Antigen-specific T cell activation depends initially on the interaction of the T cell receptor (TCR) with peptide/MHC. In addition, a costimulatory signal, mediated by distinct cell surface accessory molecules, is required for complete T cell activation leading to lymphokine production and proliferation. CD28 has been implicated as the major receptor on T cells responsible for delivering the costimulatory signal. Although two distinct ligands for CD28, B7-1 and B7-2, have been identified on antigen-presenting cells (APC), the co-stimulatory role of each molecule during a physiological immune response remains unresolved. In the present study, the relative roles of B7-1 and B7-2 interactions were evaluated in an allogeneic pancreatic islet transplant setting. In isolation, anti-B7-2 mAbs and, to a much lesser degree, anti-B7-1 mAbs suppressed T cell proliferative responses to allogeneic islets or splenic APC in vitro. Maximal inhibition of the allogeneic response was observed using a combination of the anti-B7-1 and anti-B7-2 mAbs. Administration of anti-B7-2 but not anti-B7-1 mAbs prolonged C3H allograft survival in B6 recipients, with a combination of both mAbs significantly prolonging rejection beyond either mAb alone. The immunosuppressive effects of the in vivo mAb treatment were not manifested in in vitro analyses as T cells isolated from suppressed mice responded normally to allogeneic stimuli in terms of both proliferation and lymphokine production. However, combined mAb therapy in vivo selectively delayed CD4+ T lymphocyte infiltration into the graft. These data suggest that both B7-1 and B7-2 costimulatory molecules are active in vivo, although B7-2 plays a clearly dominant role in this allograft model. The mechanism of immune suppression in vivo remains unresolved but may occur at sites distinct from the allograft.

Abatacept↗
PubMed1995

Human naive and memory T lymphocytes differ in telomeric length and replicative potential.

The present study has assessed the replicative history and the residual replicative potential of human naive and memory T cells. Telomeres are unique terminal chromosomal structures whose length has been shown to decrease with cell division in vitro and with increased age in vivo for human somatic cells. We therefore assessed telomere length as a measure of the in vivo replicative history of naive and memory human T cells. Telomeric terminal restriction fragments were found to be 1.4 +/- 0.1 kb longer in CD4+ naive T cells than in memory cells from the same donors, a relationship that remained constant over a wide range of donor age. These findings suggest that the differentiation of memory cells from naive precursors occurs with substantial clonal expansion and that the magnitude of this expansion is, on average, similar over a wide range of age. In addition, when replicative potential was assessed in vitro, it was found that the capacity of naive cells for cell division was 128-fold greater as measured in mean population doublings than the capacity of memory cells from the same individuals. Human CD4+ naive and memory cells thus differ in in vivo replicative history, as reflected in telomeric length, and in their residual replicative capacity.

Adult↗
PubMed1995

Analysis of thymic subpopulations expressing the activation antigen GL7. Expression, genetics, and function.

Previously, we reported an mAb, GL7, that defines an activation Ag expressed by in vitro-stimulated B and T cells as well as by a subpopulation of thymocytes. The current study analyzes the GL7-expressing populations of adult and fetal thymus and demonstrates that: 1) The majority of GL7+ adult thymocytes are CD4+CD8- cells that are CD3 epsilon high, TCR-alpha beta high, HSAlow, and bimodal for CD69 expression. The 3G11-6C10- subset of CD4+CD8- thymocytes is enriched in GL7-expressing cells. 2) Strain differences exist in the expression of GL7 on adult CD4+CD8- thymocytes; 21.9 +/- 5.9% of BALB/c CD4+CD8- thymocytes are GL7+, whereas 4.4 +/- 1.7% of C57BL/6 CD4+CD8- thymocytes are GL7+. The low GL7 expression phenotype is dominant in CB6F1 thymocytes (7.0 +/- 2.0%), and analysis of BALB/c x CB6F1 mice suggests that low GL7 expression is determined by multiple genes. 3) CD4+CD8- GL7+ thymocytes from BALB/c mice, but not C57BL/6 mice, are skewed toward a high proportion of V beta 8+ cells. 4) Adult GL7+ CD4+CD8- thymocytes can be activated by TCR-specific stimuli to proliferate and to secrete high amounts of IL-4. 5) Fetal thymocytes contain GL7+ cells, which are predominantly CD4-CD8-, HSAlow, CD69-, and bimodal for TCR-gamma delta. Thus, GL7 expression defines a subpopulation of functionally competent TCR-alpha beta+ CD4+CD8- thymocytes as well as TCR-gamma delta+ and TCR- subpopulations of fetal CD4-CD8- thymocytes.

Animals↗
PubMed1995

Analysis of antigen receptor signaling in B cells from mice with a retrovirus-induced acquired immunodeficiency syndrome.

MAIDS is a retrovirus-induced immunodeficiency syndrome in mice that has similarities to human AIDS. Because the functional defects in B cells from retroviral immunodeficiency syndromes have not been characterized in detail, we examined early and late parameters of B cell responses to IgM cross-linking in B cells from MAIDS and normal mice. Splenic B cells from mice with MAIDS have defective in vitro proliferative responses to LPS and anti-IgM-mediated stimuli, as well as to PMA plus calcium ionophore, indicating a generalized defect in proliferative response potential independent of specific receptor-mediated signaling. When early signaling parameters were analyzed in response to IgM cross-linking, it was found that calcium flux in B cells from MAIDS mice was significantly reduced; this reduction was not accounted for by quantitative differences in cell-surface IgM expression and therefore indicates a defect in early signal transduction through the IgM receptor. The tyrosine phosphorylation response to IgM cross-linking was also markedly deficient; tyrosine phosphorylation of Ig-alpha, Ig-beta, and an undefined protein of 80 kDa was detected in MAIDS B cells after anti-IgM stimulation, at levels substantially less than those observed in normal B cells. Multiple other tyrosine phosphorylation events observed in normal B cells, including phosphorylation of GTPase-activating protein, P13-kinase, and syk kinase, were not detected in MAIDS B cells in response to IgM cross-linking. The defect in tyrosine phosphorylation seemed to correlate with reduced surface IgM levels on a subpopulation of MAIDS B cells. B cells from mice expressing the MAIDS retrovirus-induced immunodeficiency thus reflect defects in early signaling through the Ag-specific IgM receptor as well as a generalized defect in proliferative responsiveness.

Animals↗
PubMed1995

Superantigenic characteristics of mouse mammary tumor viruses play a critical role in susceptibility to infection in mice.

Mouse mammary tumor viruses (MMTV) are retroviruses that induce mammary carcinomas. An interesting feature of these viruses is the superantigen (SAg) encoded in an open reading frame within the 3' long terminal repeat. The mechanism by which ingestion of milk-borne virus results in infection of the host mammary tissue remains incompletely understood. However, a working model has been proposed in which the interaction between viral SAg, T-cell receptor and MHC class II I-E facilitates viral replication and hence infectivity. In this review we summarize current studies demonstrating the role of SAg stimulation in susceptibility to MMTV infection.

Animals↗
PubMed1994

The tissue distribution of the B7-2 costimulator in mice: abundant expression on dendritic cells in situ and during maturation in vitro.

B7-2 is a recently discovered, second ligand for the CTLA-4/CD28, T cell signaling system. Using the GL-1 rat monoclonal antibody (mAb), we monitored expression of B7-2 on mouse leukocytes with an emphasis on dendritic cells. By cytofluorography, little or no B7-2 was detected on most cell types isolated from spleen, thymus, peritoneal cavity, skin, marrow, and blood. However, expression of B7-2 could be upregulated in culture. In the case of epidermal and spleen dendritic cells, which become highly immunostimulatory for T cells during a short period of culture, the upregulation of B7-2 was dramatic and did not require added stimuli. Lipopolysaccharide did not upregulate B7-2 levels on dendritic cells, in contrast to macrophages and B cells. By indirect immunolabeling, the level of staining with GL-1 mAb exceeded that seen with rat mAbs to several other surface molecules including intercellular adhesion molecule 1, B7-1, CD44, and CD45, as well as new hamster mAbs to CD40, CD48, and B7-1/CD80. Of these accessory molecules, B7-2 was a major species that increased in culture, implying a key role for B7-2 in the functional maturation of dendritic cells. B7-2 was the main (> 90%) CTLA-4 ligand on mouse dendritic cells. When we applied GL-1 to tissue sections of a dozen different organs, clear-cut staining with B7-2 antigen was found in many. B7-2 staining was noted on liver Kupffer cells, interstitial cells of heart and lung, and profiles in the submucosa of the esophagus. B7-2 staining was minimal in the kidney and in the nonlymphoid regions of the gut, and was not observed at all in the brain. In the tongue, only rare dendritic cells in the oral epithelium were B7-2+, but reactive cells were scattered about the interstitial spaces of the muscle. In all lymphoid tissues, Gl-1 strongly stained certain distinct regions that are occupied by dendritic cells and by macrophages. For dendritic cells, these include the thymic medulla, splenic periarterial sheaths, and lymph node deep cortex; for macrophages, the B7-2-rich regions included the splenic marginal zone and lymph node subcapsular cortex. Splenic B7-2+ cells were accessible to labeling with GL-1 mAb given intravenously. Dendritic cell stimulation of T cells (DNA synthesis) during the mixed leukocyte reaction was significantly (35-65%) blocked by GL-1.(ABSTRACT TRUNCATED AT 400 WORDS)

Abatacept↗