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Studies on human type 1 diabetes (T1D) are facilitated by the availability of animal models such as nonobese diabetic (NOD) mice that spontaneously develop autoimmune diabetes, as well as a variety of genetically engineered mouse models with reduced genetic and pathogenic complexity, as compared to the spontaneous NOD model. In recent years, increasing evidence has implicated CD4+CD25+ regulatory T (Treg) cells expressing the transcription factor Foxp3 in both the breakdown of self-tolerance and the restoration of immune homeostasis in T1D. In this paper, we provide an overview of currently available mouse models to study the role of Foxp3+ Treg cells in the control of destructive β cell autoimmunity, including a novel NOD model that allows specific and temporally controlled deletion of Foxp3+ Treg cells. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Pedersen et al. (2011) Matrix-M adjuvanted virosomal H5N1 vaccine confers protection against lethal viral challenge in a murine model. Influenza and Other Respiratory Viruses 5(6), 426-437. Background A candidate pandemic influenza H5N1 vaccine should provide rapid and long-lasting immunity against antigenically drifted viruses. As H5N1 viruses are poorly immunogenic, this may require a combination of immune potentiating strategies. An attractive approach is combining the intrinsic immunogenicity of virosomes with another promising adjuvant to further boost the immune response. As regulatory authorities have not yet approved a surrogate correlate of protection for H5N1 vaccines, it is important to test the protective efficacy of candidate H5N1 vaccines in a viral challenge study. Objectives This study investigated in a murine model the protective efficacy of Matrix-M adjuvanted virosomal influenza H5N1 vaccine against highly pathogenic lethal viral challenge. Methods Mice were vaccinated intranasally (IN) or intramuscularly (IM) with 7·5 μg and 30 μg HA of inactivated A/Vietnam/1194/2004 (H5N1) (NIBRG-14) virosomal adjuvanted vaccine formulated with or without 10 μg of Matrix-M adjuvant and challenged IN with the highly pathogenic A/Vietnam/1194/2004 (H5N1) virus. Results and conclusions IM vaccination provided protection irrespective of dose and the presence of Matrix-M adjuvant, whilst the IN vaccine required adjuvant to protect against the challenge. The Matrix-M adjuvanted vaccine induced a strong and cross-reactive serum antibody response indicative of seroprotection after both IM and IN administration. In addition, the IM vaccine induced the highest frequencies of influenza specific CD4+ and CD8+ T-cells. The results confirm a high potential of Matrix-M adjuvanted virosomal vaccines and support the progress of this vaccine into a phase 1 clinical trial. [ABSTRACT FROM AUTHOR]

OTHER ARTICLES PUBLISHED IN THIS MINI-REVIEW SERIES ON Th17 CELLS Function and regulation of human T helper 17 cells in health and disease. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04037.x Induction of interleukin-17 production by regulatory T cells. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04038.x Are T helper 17 cells really pathogenic in autoimmunity? Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04039.x CD4+ T helper cells: functional plasticity and differential sensitivity to regulatory T cell-mediated regulation. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04040.x There has been a considerable amount of interest in the immunological community about new phenotypic subsets of CD4+ T cells, particularly cells that produce the cytokine interleukin (IL)-17 [named T helper type 17 (Th17) cells]. While the initial discovery of Th17 cells and the pathways that controlled their development was in the mouse, recent attention has shifted to the existence of these cells and the relevant upstream cytokine signals in humans. While it is clear that CD4+ T cells producing IL-17 exist in vivo, their relevance to disease pathogenesis is only just being understood. In this paper, we review the data regarding the generation of human Th17 cells in vitro and the evidence that this effector population is important in human disease states. [ABSTRACT FROM AUTHOR]

Recently, we demonstrated that C57BL/6 mice are more susceptible to experimental lagochilascariosis than BALB/c mice. To investigate the pattern of infection and the role of the genetic background on susceptibility to infection, we studied experimental lagochilascariosis in H-2a identical B10.A and A/J mice. Infected B10.A mice had a lower survival ratio and more severe lesions in the lungs than did A/J mice. Splenocytes of A/J mice immunized with the crude extract of the parasite showed increased proliferation and produced a higher level of interleukin 10 and interferon-? in the presence of CE or concanavalin A when compared to B10.A mice. This suggests that resistance of A/J mice may be due to less severe lesions in lungs and other organs and a better immune response to parasite antigens. This paper provides evidence that major histocompatibility complex haplotype does not influence the survival to experimental infection with L. minor. [ABSTRACT FROM AUTHOR]

Crohn's disease and ulcerative colitis, two major forms of inflammatory bowel disease (IBD) in humans, afflicted in genetically predisposed individuals due to dysregulated immune response directed against constituents of gut flora. The defective immune responses mounted against the regulatory mechanisms amplify and maintain the IBD-induced mucosal inflammation. Therefore, restoring the balance between inflammatory and anti-inflammatory immunepathways in the gut may contribute to halting the IBD-associated tissue-damaging immune response. Phenotypic and functional characterization of various immune-suppressive T cells (regulatory T cells; Tregs) over the last decade has been used to optimize the procedures for in vitro expansion of these cells for developing therapeutic interventional strategies. In this paper, we review the mechanisms of action and functional importance of Tregs during the pathogenesis of IBD and modulating the disease induced inflammation as well as role of mouse models including humanized mice repopulated with the human immune system (HIS) to study the IBD. "Humanized" mouse models provide new tools to analyze human Treg ontogeny, immunobiology, and therapy and the role of Tregs in developing interventional strategies against IBD. Overall, humanized mouse models replicate the human conditions and prove a viable tool to study molecular functions of human Tregs to harness their therapeutic potential. [ABSTRACT FROM AUTHOR]

Presents abstracts of research papers on intracellular signaling and development of immune cells, published in the December 2002 supplement of 'Immunology.' 'The role of src-family kinases in T-cell function,' by R. Zamoyska; 'Impaired B and T-cell antigen receptor signalling in p110delta PI 3-kinase mutant mice,' by K. Okkenhaug, et al.

This paper investigates the Vβ usage of lymph node cells from mice immunized with TNP and of cell lines made from them. In cell lines stimulated weekly with TNP in vitro for 1 month, about 87% of the cells were Vβ8+ and further analysis showed that these cells were actually Vβ.2+. This was also true for the cells that proliferated in lymph nodes in response to TNP 4 days after primary immunization, i.e. proliferation occurred mainly in the Vβ+, and in particular in the Vβ8.2+, population while much less proliferation occurred when the Vβ8- or Vβ8.2- T-cell populations are used. This was not due to non-specific damage during separation, as the response to concanavalin A and alloantigen was intact. In a separate series of experiments, mice were acutely depleted of Vβ8+ T cells by treatment with F23.1 or a control monoclonal antibody (mAb) in vivo given before immunization. Treatment with the relevant mAb virtually abolished the response to TNP. In contrast, SJL mice, which lack the gone segment coding for the Vβ8 family and several other Vβ chains, made a normal proliferative and delayed-type hypersensitivity (DTH) response to TNP. This poses the problem, which may he important in the study of the T-cell repertoire, of why acute removal of Vβ8+ T cells, which are dominantly used in the response to TNP, does not allow T cells using other chains to substitute in the response, while the absence of this population over a long period of time, because of a deletion in the genome, allows the use of T cells hearing other Vβ chains. [ABSTRACT FROM AUTHOR]

In different murine systems, delayed-type hypersensitivity (DTH) swelling responses at 24–48 hr after antigen challenge were preceeded by an early 2-hr swelling response. The 24-hr DTH response is thought to depend on this early (DTH-initiating) hypersensitivity response. In this paper we show that in the syngeneic DBA/2-SL2 routine turnout system only an early 2-hr swelling response can be evoked. This early hypersensitivity response was tumour specific and serotonin dependent. The early hypersensitivity response in contact hypersensitivity has been ascribed to antigen-specific T-cell factors. To test whether similar T-cell factors were involved in the early hypersensitivity response in this syngencic turnout system, we have transferred lymph node, spleen lymphocytes and scram from immunized mice into naive recipients. The serum was fractionated in two fractions, a 50,000–80,000 MW fraction, and a 120,000–190,000 MW fraction. In recipients of lymphocytes, total serum and the 50,000–80,000 MW fraction of the serum, an early hypersensitivity response can be evoked. So, these data suggest the involvement of specific T-cell factors in the development of an early hypersensitivity response against syngeneic tumour cells. Despite the development of an early (DTH initiating) hypersensitivity swelling response these immunized animals cannot develop a classical 24-hr swelling response. This absence of the 24-hr response in the presence of the 2-hr response is discussed in relation to the frequently observed immune suppression in tumour-bearing mice. [ABSTRACT FROM AUTHOR]

Previous work from this laboratory has shown that preimmunization of syngeneic hosts with Rous sarcoma virus (RSV)-transformed cells elicits a strong immune response against the growth of transplantable RSV sarcomas, mediated by T lymphocytes expressing the surface phenotype of helper cell precursors (Prat, Di Renzo & Comoglio, 1983). This paper shows that anti-tumour immunity may be elicited in tumour-bearing animals by triggering an experimentally pre-amplified T-helper cell population at the site of tumour growth. Mice were treated with cyclophosphamide (which inactivates suppressor T cells) followed by skin sensitization to trinitrochlorobenzene (TNCB) according to a protocol that has been shown to induce an appreciably amplified generation of trinitrophenyl (TNP)-reactive helper T cells (Fujiwara et al., 1984). Five weeks after TNCB painting, mice were transplanted s.c. with a lethal dose of RSV-induced syngeneic sarcoma cells; the injection at the tumour site of TNCB induced the regression of the tumour in mice in which the TNP-helper cell population has been amplified, but not in controls, including those injected with a non-related hapten or sensitized to TNCB without inactivation of suppressors. [ABSTRACT FROM AUTHOR]

Although different models for rheumatoid arthritis have been studied, the pathogenesis in humans remains unknown. A possible mechanism is the crossreactivity between bacterial components and the target-tissue, the cartilage. The existence of this crossreactivity is supported by various data from clinical and experimental studies. Here we provide direct evidence that priming in vivo with cell wall fragments of Streptococcus pyogenes or Escherichia coli can induce a cellular and humoral anti-cartilage response in Balb/c mice in vitro. T cells isolated from these mice can be stimulated in vivo to proliferate by a variety of antigens among which arc the priming bacterium, an unrelated bacterium, small bacterial components and diverse antigens of cartilagenous origin. In bacterium-primed mice antibodies were also detected that displayed a reactivity to cartilage extract besides the reactivity to bacteria. A crossreactive response occurred in vivo in certain circumstances; a delayed type hypersensitivity reaction could be elicited in cell-wall-primed mice by challenge with cartilage extract. For the expression of this crossreactive response in vivo however, it was obligatory to attenuate the mouse's suppressor-circuit. In this paper we would suggest a mechanism for the pathology of chronic arthritis, based on repeated challenges with different bacterial stimuli. [ABSTRACT FROM AUTHOR]

The responses of thymocytes to Coneanavalin A (Con A), and interleukin 1 (IL-1), interleukin 2 (IL-2) and phorbol myristate acetate (PMA) were investigated. The enzyme 20-a-hydroxysteroid dehydrogenase (20αSDH) was used as a marker to distinguish between various populations of activated thymocytes. Thymocytes that were selected in Con A + pure or crude IL-2 expressed high 20αSDH activity, while those that were selected in Con A + recombinant IL-1 (rIL-1) or crude IL-1, or Con A + PMA expressed low 20αSDH activity. Both groups proliferate in response to Con A and had IL-2 receptors. After selection, the enzymatic phenotype was stable even if the cells were transferred from Con A + IL-2 to Con A + PMA (or IL-1) or vice versa. A third group was selected from thymocytes that were cultured in PMA + T cell growth factor (TCGF). This group expressed low levels of 20αSDH, had IL-2 receptors, but did not respond to Con A. This paper demonstrates that 20αSDH can be used as an enzymatic marker to distinguish between subpopulations of activated T cells, which have not been previously detected by the conventional surface markers. [ABSTRACT FROM AUTHOR]

The article comments on a paper by M. A. Freise examining the mechanistic basis for risk for multiple sclerosis associated with HLA class I alleles, which are recognized by CD8+ cytotoxic T cells. According to the author, the paper demonstrates in humanized transgenic mice that CD8+ T cells can induce a multiple sclerosis-like disease and that the HLA class I molecules can confer either risk or protection.