Robinson R.T.,Medical College of Wisconsin |
Orme I.M.,Colorado State University |
Cooper A.M.,Trudeau Institute
Immunological Reviews | Year: 2015
Mycobacterium tuberculosis (Mtb) has been evolving with its human host for over 50 000 years and is an exquisite manipulator of the human immune response. It induces both a strong inflammatory and a strong acquired immune response, and Mtb then actively regulates these responses to create an infectious lesion in the lung while maintaining a relatively ambulatory host. The CD4+ T cell plays a critical yet contradictory role in this process by both controlling disseminated disease while promoting the development of the lesion in the lung that mediates transmission. In light of this manipulative relationship between Mtb and the human immune response, it is not surprising that our ability to vaccinate against tuberculosis (TB) has not been totally successful. To overcome the current impasse in vaccine development, we need to define the phenotype of CD4+ T cells that mediate protection and to determine those bacterial and host factors that regulate the effective function of these cells. In this review, we describe the initiation and expression of T cells during TB as well as the fulminant inflammatory response that can compromise T-cell function and survival. © 2015 John Wiley & Sons A/S.
Haynes L.,Trudeau Institute |
Parker C.,Academic Urology Unit |
Iversen P.,Copenhagen University
Journal of the National Cancer Institute | Year: 2012
Sipuleucel-T was approved by the US Food and Drug Administration on April 29, 2010, as an immunotherapy for late-stage prostate cancer. To manufacture sipuleucel-T, mononuclear cells harvested from the patient are incubated with a recombinant prostatic acid phosphatase (PAP) antigen and reinfused. The manufacturer proposes that antigen-presenting cells exogenously activated by PAP induce endogenous T-cells to attack PAP-bearing prostate cancer cells. However, the lack of demonstrable tumor responses has prompted calls for scrutiny of the design of the trials in which sipuleucel-T demonstrated a 4-month survival benefit. Previously unpublished data from the sipuleucel-T trials show worse overall survival in older vs younger patients in the placebo groups, which have not been shown previously to be prognostic for survival in castration-resistant prostate cancer patients receiving chemotherapy. Because two-thirds of the cells harvested from placebo patients, but not from the sipuleucel-T arm, were frozen and not reinfused a detrimental effect of this large repeated cell loss provides a potential alternative explanation for the survival "benefit." Patient safety depends on adequately addressing this alternative explanation for the trial results. © 2012 The Author (s). Published by Oxford University Press.
Lefebvre J.S.,Trudeau Institute |
Haynes L.,Trudeau Institute
Current Opinion in Immunology | Year: 2013
The elderly population is more susceptible to infections with higher risks of morbidity and mortality. This is caused by the accumulation of immune defects with aging. The best way to protect people against infections is vaccination. Unfortunately, the same immune defects that render the elderly susceptible to infectious diseases also prevent the development of protective immunity following immunization. A good example of this is the influenza vaccine that only protects between 40 and 60% of the vaccinees over 65 years. In the past decade, tremendous efforts have been put toward improving the influenza vaccine for the elderly. We therefore use this example to present various strategies employed to overcome these age-associated immune defects and hence make vaccines more efficacious for the aged. © 2013 Elsevier Ltd.
Haynes L.,Trudeau Institute |
Swain S.L.,University of Massachusetts Medical School
Seminars in Immunology | Year: 2012
Our recent studies indicate that the longer peripheral persistence of naïve CD4 T cells that occurs with age is necessary for the development of the key aging defects that lead to compromised responses to vaccination and to new pathogens or new strains of circulating infectious agents. This longer persistence is in turn is linked to the decrease in development of new thymic emigrants and thymic involution that occur at adolescence. Therefore the process of development of naïve CD4 aging defects, is closely tied to the homeostasis of T cells and the shifts that occur in their homeostasis with age. Here we review this connection between age-related changes in T cell homeostasis and the development of T cell defects and discuss the implication for approaches to better vaccinating the elderly. © 2012 Elsevier Ltd.
Blackman M.A.,Trudeau Institute |
Woodland D.L.,Trudeau Institute
Current Opinion in Immunology | Year: 2011
Immune function declines progressively with age, resulting in increased susceptibility of the elderly to infection and impaired responses to vaccines. A diverse repertoire of T cells is essential for a vigorous immune response, and an important manifestation of immune aging is the progressive loss of repertoire diversity, predominantly among CD8 T cells in both mice and humans. Importantly, perturbations in the peripheral T cell repertoire, including reduction of the CD4:CD8 ratio and cytomegalovirus-driven T cell clonal expansions, make a major contribution to the 'immune risk phenotype' defined for humans, which predicts two-year mortality in very old individuals. © 2011 Elsevier Ltd.
Vomhof-DeKrey E.E.,Trudeau Institute |
Yates J.,Trudeau Institute |
Leadbetter E.A.,Trudeau Institute
Current Opinion in Immunology | Year: 2014
B cells rely on CD4+ T cells helper signals to optimize their responses to T-dependent antigens. Recently another subset of T cells has been identified which provides help for B cells, invariant natural killer T (iNKT) cells. iNKT cells are unique because they provide both innate and adaptive forms of help to B cells, with divergent outcomes. iNKT cells are widely distributed throughout the spleen at rest, consolidate in the marginal zone of the spleen early after activation, and are later found in germinal centers. Understanding the activation requirements for iNKT cells has led to the development of glycolipid containing nanoparticles which efficiently activate iNKT cells, enhance their cooperation with B cells, and which hold promise for vaccine development. © 2014 Elsevier Ltd.
Pearce E.L.,Trudeau Institute
Current Opinion in Immunology | Year: 2010
When naïve or memory T cells encounter foreign antigen along with proper co-stimulation they undergo rapid and extensive clonal expansion. In mammals, this type of proliferation is fairly unique to cells of the adaptive immune system and requires a considerable expenditure of energy and cellular resources. While research has often focused on the roles of cytokines, antigenic signals, and co-stimulation in guiding T cell responses, data indicate that, at a fundamental level, it is cellular metabolism that regulates T cell function and differentiation and therefore influences the final outcome of the adaptive immune response. This review will focus on some earlier fundamental observations regarding T cell bioenergetics and its role in regulating cellular function, as well as recent work that suggests that manipulating the immune response by targeting lymphocyte metabolism could prove useful in treatments against infection and cancer. © 2010 Elsevier Ltd.
Cooper A.M.,Trudeau Institute |
Mayer-Barber K.D.,Laboratory of Parasitic Diseases |
Sher A.,Laboratory of Parasitic Diseases
Mucosal Immunology | Year: 2011
Cells of the innate immune system produce cytokines and lipid mediators that strongly influence the outcome of mycobacterial infection. In the case of Mycobacterium tuberculosis, the lung is a critical site for this interaction. Here, we review current information on the role of the major innate cytokine pathways both in controlling initial infection as well as in promoting and maintaining adaptive T-cell responses that mediate host resistance or immunopathology. Understanding this important feature of the host-pathogen interaction can provide major insights into the mechanisms of virulence and can lead to new approaches for immunological intervention in tuberculosis and other mycobacterial diseases. © 2011 Society for Mucosal Immunology.
Trudeau Institute | Date: 2011-10-20
This invention relates to vaccine formulations comprising the Yersinia pestis YopE peptide antigen or subparts thereof. The invention also relates to methods of vaccinating subjects at risk of Yersinia pestis infection as well as assays for measuring immune response to plague vaccines.
Trudeau Institute | Date: 2011-02-07
The present invention describes compositions for both diagnostic and therapeutic applications. In one embodiment, the present invention contemplates a vaccine formulation comprising an antigen and IL12R1 isoform 2. In some embodiments, this invention relates to a method of quantifying the ratio of IL12R1 transcript and a splice variant thereof in a sample, including but not limited to at the cDNA level. In other embodiments, this invention relates to a method of augmenting an immune response by administering, inhibiting and/or inducing IL12R1 isoform 2.