210 research outputs found
Detection of autoreactive T cells in H-2(u) mice using peptide-MHC multimers
No full textMyelin basic protein (MBP)-specific T cells play a critical role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a prototype for T cell-mediated autoimmunity. In PL/J and B10.PL mice (H-2(u) haplotype), the immunodominant epitope of MBP is represented by an N-terminal nonameric peptide, MBP1-9. To date, the MBP1-9-specific T cell repertoire has not been analyzed in quantitative terms. In the present study we demonstrate, using MHC class II tetramers, that 15,000-70,000 self-antigen-specific T(h) cells accumulate in the draining lymph nodes following immunization with spinal cord homogenate or MBP1-9. In contrast, MBP1-9-specific T cells are undetectable in unimmunized H-2(u) mice and represent >60% of the CD4 cells in naive mice transgenic for a TCR specific for this epitope. The results suggest that the extremely low affinity of the N-terminal peptide for I-A(u) does not limit the MBP1-9-specific T cells from expanding into a sizeable pool of autoreactive T cells. Therefore, the primary immune response to MBP1-9 does not differ quantitatively from previously reported CD4+ T cell responses to foreign antigens.</p
Negative selection during the peripheral immune response to antigen
No full textThymic selection depends on positive and negative selective mechanisms based on the avidity of T cell interaction with antigen-major histocompatibility Complex complexes. However, peripheral mechanisms for the recruitment and clonal expansion of the responding T cell repertoire remain obscure. Here we provide evidence for an avidity-based model of peripheral T cell clonal expansion in response to antigenic challenge. We have used the encephalitogenic, H-2 Au-restricted, acetylated NH2-terminal nonameric peptide (Ac1-9) epitope from myelin basic protein as our model antigen. Peptide analogues were generated that varied in antigenic strength (as assessed by in vitro assay) based on differences in their binding affinity for Au. In vivo, these analogues elicited distinct repertoires of T cells that displayed marked differences in antigen sensitivity. Immunization with the weakest (wild-type) antigen expanded the high affinity T cells required to induce encephalomyelitis. In contrast, immunization with strongly antigenic analogues led to the elimination of T cells bearing high affinity T cell receptors by apoptosis, thereby preventing disease development. Moreover, the T cell repertoire was consistently tuned to respond to the immunizing antigen with the same activation threshold. This tuning mechanism provides a peripheral control against the expansion of autoreactive T cells and has implications for immunotherapy and vaccine design.</p
Long-term follow-up of endurance and safety outcomes during enzyme replacement therapy for mucopolysaccharidosis VI: Final results of three clinical studies of recombinant human N-acetylgalactosamine 4-sulfatase
No full textCopyright © 2008 Elsevier Inc. All rights reserved.UnlabelledThe objective of this study was to evaluate the long-term clinical benefits and safety of recombinant human arylsulfatase B (rhASB) treatment of mucopolysaccharidosis type VI (MPS VI: Maroteaux-Lamy syndrome), a lysosomal storage disease. Fifty-six patients derived from 3 clinical studies were followed in open-label extension studies for a total period of 97-260 Weeks. All patients received weekly infusions of rhASB at 1 mg/kg. Efficacy was evaluated by (1) distance walked in a 12-minute walk test (12MWT) or 6-minute walk test (6MWT), (2) stairs climbed in the 3-minute stair climb (3MSC), and (3) reduction in urinary glycosaminoglycans (GAG). Safety was evaluated by compliance, adverse event (AE) reporting and adherence to treatment.ResultsA significant reduction in urinary GAG (71-79%) was sustained. For the 12MWT, subjects in Phase 2 showed improvement of 255+/-191 m (mean+/-SD) at Week 144; those in Phase 3 Extension demonstrated improvement from study baseline of 183+/-26 m (mean+/- SE) in the rhASB/rhASB group at Week 96 and from treatment baseline (Week 24) of 117+/-25 m in the placebo/rhASB group. The Phase 1/2 6MWT and the 3MSC from Phase 2 and 3 also showed sustained improvements through the final study measurements. Compliance was 98% overall. Only 560 of 4121 reported AEs (14%) were related to treatment with only 10 of 560 (2%) described as severe.ConclusionrhASB treatment up to 5 years results in sustained improvements in endurance and has an acceptable safety profile.Paul Harmatz, Roberto Giugliani, Ida Vanessa D. Schwartz, Nathalie Guffon, Elisa Leão Teles, M. Clara Sá Miranda, J. Edmond Wraith, Michael Beck, Laila Arash, Maurizio Scarpa, David Ketteridge, John J. Hopwood, Barbara Plecko, Robert Steiner, Chester B. Whitley, Paige Kaplan, Zi-Fan Yu, Stuart J. Swiedler, Celeste Decker and for the MPS VI Study Grouphttp://www.elsevier.com/wps/find/journaldescription.cws_home/622920/description#descriptio
Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs
No full textTregs are important mediators of immune tolerance to self antigens, and it has been suggested that Treg inactivation may cause autoimmune disease. Therefore, immunotherapy approaches that aim to restore or expand autoantigen-specific Treg activity might be beneficial for the treatment of autoimmune disease. Here we report that Treg-mediated suppression of autoimmune disease can be achieved in vivo by taking advantage of the ability of the liver to promote immune tolerance. Expression of the neural autoantigen myelin basic protein (MBP) in the liver was accomplished stably in liver-specific MBP transgenic mice and transiently using gene transfer to liver cells in vivo. Such ectopic MBP expression induced protection from autoimmune neuroinflammation in a mouse model of multiple sclerosis. Protection from autoimmunity was mediated by MBP-specific CD4+CD25+Foxp3+ Tregs, as demonstrated by the ability of these cells to prevent disease when adoptively transferred into nontransgenic mice and to suppress conventional CD4+CD25- T cell proliferation after antigen-specific stimulation with MBP in vitro. The generation of MBP-specific CD4+CD25+Foxp3+ Tregs in vivo depended on expression of MBP in the liver, but not in skin, and occurred by TGF-beta-dependent peripheral conversion from conventional non-Tregs. Our findings indicate that autoantigen expression in the liver may generate autoantigen-specific Tregs. Thus, targeting of autoantigens to hepatocytes may be a novel approach to prevention or treatment of autoimmune diseases
The Future of Immunotherapy: A 20-Year Perspective
No full textImmunotherapy is the field of immunology that aims to identify treatments for diseases through induction, enhancement or suppression of an immune response. Immunotherapies designed to instigate or enhance an immune response are considered “activating immunotherapies” while those designed to repress an immune response are “suppressive immunotherapies.” This perspective will focus on two areas of immunotherapy, activating immunotherapies for cancer and suppressive immunotherapies for autoimmunity both of which have seen a resurgence in interest in recent years and are likely to transform the treatment of many human diseases in the next 20 years. Effective immunotherapies for cancer, where the aim is to activate tumor-specific immune responses, will be totally different from those designed to suppress the immune response to self-antigens in autoimmune disease. Furthermore, the reader will appreciate that the degree to which side effects of immunotherapies are acceptable will differ drastically between life-threatening cancers and chronic, debilitating but not necessarily life-threatening autoimmune conditions
The psychological implications of surviving testicular cancer : impact on body image, sexuality and masculinity
No full textINTRODUCTION:
Men's health generally and testicular cancer in particular are neglected areas of research. This particular malignancy is the most common among young men in the western world (Champion, 1996), and its prevalence is on the increase, however, so too are cure rates. As a consequence there are an increasing number of young male survivors. Impact on sexual function of survivors is well documented in the literature, yet little is mentioned about the impact on the sexuality and masculinity of the young man following treatment. The objective of the research therefore was to explore the impact on survivor's self-perceptions,in particular focusing on the areas of sexuality, masculinity and body image.
METHOD:
The research followed a cross-sectional design,
comparing men at four different stages post-illness. Repertory grid technique was utilised for data collection
purposes, which combined qualitative and quantitative methods. Semi-structured interviews (n = 10) were analysed using content analysis, which formed the basis of a
generic repertory grid. Quantitative data from subsequent grid completion (n = 37)were analysed using a beta version of SPSS to carry out 3-way 3-mode multidimensional unfolding.
RESULTS:
The results suggest that men's self-perceptions change as a consequence of testicular cancer, and that sexuality, masculinity and body image play a part in these changes for some, but not all men. The constructs rated in this study all contribute to the differences in patterns across groups. Results suggest the occurrence of an adjustment process, showing current perceptions of the self as more aligned with retrospective pre-illness perceptions by 24 months post-illness. The majority of men judged repertory grid technique to be a satisfactory means of evaluating self-perceptions relating to the illness experience.
DISCUSSION:
The results of the study have implications for the level of professional support received by men with testicular cancer, both generally and with specific reference to issues of sexuality, masculinity and body image. However the innovative style of this research and the absence of pre-existing evidence in support of the findings, mean that further research will be required to gain a thorough understanding of the psychological implications of surviving testicular cancer with regards to these issues. Specific recommendations are made for further researc
Designing antigens for the prevention and treatment of autoimmune diseases
No full textAntigen-specific immunotherapy is considered the holy-grail for treatment of autoimmune diseases. However, unlike the unattainable myth of Arthurian legend, effective antigen-specific immunotherapy is now being realised through clinical trials in patients. This review describes the various approaches being taken, how antigens are being designed for therapy and carriers created for their delivery. A critical assessment is made concerning the need for such carrier systems.</p
Avidity and the Art of Self Non-Self Discrimination
No full textMuch has been learned since Jan Klein first defined immunology as the “science of self non-self discrimination.” A paper in this issue of Immunity provides important insight into how such discrimination is achieved (Zehn and Bevan, 2006)
Blockade of LFA-1 augments in vitro differentiation of antigen-induced Foxp3+ Treg cells
No full textAbstractAdoptive transfer of antigen-specific, in vitro-induced Foxp3+ Treg (iTreg) cells protects against autoimmune disease. To generate antigen-specific iTreg cells at high purity, however, remains a challenge. Whereas polyclonal T cell stimulation with anti-CD3 and anti-CD28 antibody yields Foxp3+ iTreg cells at a purity of 90–95%, antigen-induced iTreg cells typically do not exceed a purity of 65–75%, even in a TCR-transgenic model. In a similar vein to thymic Treg cell selection, iTreg cell differentiation is influenced not only by antigen recognition and the availability of TGF-β but also by co-factors including costimulation and adhesion molecules. In this study, we demonstrate that blockade of the T cell integrin Leukocyte Function-associated Antigen-1 (LFA-1) during antigen-mediated iTreg cell differentiation augments Foxp3 induction, leading to approximately 90% purity of Foxp3+ iTreg cells. This increased efficacy not only boosts the yield of Foxp3+ iTreg cells, it also reduces contamination with activated effector T cells, thus improving the safety of adoptive transfer immunotherapy
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