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Biomedical subjects

A N Akbar

Publications and source records attributed to A N Akbar.

At least 19 recordsLinked to original sources
PubMed2005

Peripheral generation and function of CD4+CD25+ regulatory T cells.

The balance between immunity and tolerance is important to maintain immune homeostasis. Several mechanisms are in place to ensure that the immune response is controlled, such as T cell anergy, apoptosis and immune ignorance. A fourth mechanism of peripheral tolerance is the active suppression by regulatory or suppressor T cells. The existence of suppressor T cells was first described in the early 1970s, but these cells became discredited in the 1980s. The work of Shimon Sakaguchi and others, however, has brought these cells back into the limelight and nowadays research into regulatory/suppressor T cells is a very active field of immunology. Different types of regulatory T cells have been described, including CD4+CD25+ T cells that constitutively express CTLA-4, GITR and Foxp3, TGF-beta producing Th3 cells, IL-10 producing Tr1 cells, and CD8+CD28- T cells. This review will focus on the generation and function of CD4+CD25+ regulatory T cells. CD4+CD25+ regulatory cells were originally described as thymus-derived anergic/suppressive T cells. Recent papers, however, indicate that these cells might also be generated in the periphery. CD4+CD25+ regulatory T cells can be activated by self-antigens and non-self-antigens, and once activated can suppress T cells in an antigen nonspecific manner. Interestingly, the suppressive effects of these cells are not restricted to the adaptive immune system (T and B cells) but can also affect the activation and function of innate immune cells (monocytes, macrophages, dendritic cells). These features make the CD4+CD25+ regulatory T cell subset an interesting target for immunotherapy of chronic inflammatory or autoimmune diseases.

Animals↗
PubMed2005

The immunomodulatory effects of regulatory T cells: implications for immune regulation in the skin.

Regulatory T cells are thought to have a critical role in the suppression of immune responses. In addition to the prevention of the development of autoimmunity, they are also thought to have a role in the prevention of allergic responses to environmental allergens, immune responses to tumours and the development of memory responses to chronic infections. They have been isolated within the skin and have been shown to express surface markers that enable skin-specific migration, suggesting that regulatory T cells have a functional role in the skin. There is accumulating evidence to suggest that regulatory T cells may be involved in numerous skin disorders and may also be modified by various therapeutic agents used to treat these disorders. We review the evidence for the presence of this T-cell subset in humans, the suppressive effects of regulatory T cells, and their role in the skin.

Drug Eruptions↗
PubMed2005

Relative impact of CD4+CD25+ regulatory T cells and tacrolimus on inhibition of T-cell proliferation in patients with atopic dermatitis.

BACKGROUND: It has been established recently that CD4+CD25+ regulatory T cells (Tregs) play an important role in controlling various immune responses. Immunosuppressive drugs are often used to treat immune dysregulation but are frequently associated with undesirable side-effects. OBJECTIVES: We examined the suppressive capacity of circulating Tregs in patients with atopic dermatitis (AD). Combined effects of Tregs and tacrolimus on the inhibition of T-cell proliferation in vitro were also assessed. METHODS: CD4+CD25+ and CD4+CD25- T cells were isolated from peripheral blood mononuclear cells using immunomagnetic beads. CD4+CD25- T cells were stimulated with purified protein derivative (PPD) or house dust mite allergen (Der p1) for 6 or 7 days, respectively. A dose range of tacrolimus and CD4+CD25+ T cells were added separately, or together. Proliferation was measured by (3)H-thymidine incorporation. RESULTS: CD4+CD25+ T cells from normal controls and patients with AD are anergic and inhibit the proliferation of CD4+CD25- T cells in response to PPD and Der p1 in vitro in a dose-dependent manner. Addition of tacrolimus and Tregs together showed significantly stronger inhibition of proliferation than either on their own. This was true for both antigens and both in normal controls and in patients with AD. CONCLUSIONS: CD4+CD25+ T cells in patients with AD have normal suppressive activity compared with healthy controls. Tregs and tacrolimus have additive effects on the inhibition of proliferation in response to PPD and Der p1.

Antigens, Dermatophagoides↗
PubMed2004

T lymphocyte mediated lysis of mitomycin C treated Tenon's capsule fibroblasts.

AIMS: To evaluate the effect of T cell co-culture on mitomycin C treated and untreated Tenon's capsule fibroblasts. METHODS: IL-2 dependent allogeneic T cells were incubated over a monolayer of mitomycin C treated or control fibroblasts. Fibroblast numbers were evaluated by direct counts using phase contrast microscopy. To determine whether T cell mediated lysis was a consequence of MHC mismatch, co-culture experiments were repeated with autologous T cells. The effect of Fas receptor blockade was established by co-incubation with a Fas blocking (M3) antibody. RESULTS: T cell co-culture resulted in a dramatic reduction in fibroblast survival compared to mitomycin C treatment alone (p = 0.032). T cell killing required fibroblast/lymphocyte cell to cell contact and was observed in both allogeneic and autologous co-culture experiments. Fas blocking antibodies did not significantly inhibit T cell killing (p = 0.39). CONCLUSION: T cells augment mitomycin C treated fibroblast death in vitro. Similar mechanisms may contribute to the cytotoxic effect of mitomycin C in vivo and account for the largely hypocellular drainage blebs that are observed clinically.

Antibiotics, Antineoplastic↗
PubMed2002

In vivo production of interferon beta by human Tenon's fibroblasts; a possible mediator for the development of chronic conjunctival inflammation.

BACKGROUND: Chronic inflammation may develop from failure of the immune system to deactivate itself during resolution of the wound healing response, and is recognised as a major risk factor for trabeculectomy failure. Fibroblast/T cell interactions may contribute to aggressive scarring. Our previous research showed that in vitro human Tenon's fibroblast produced interferon beta was responsible for preventing T cell apoptosis, suggesting that this interaction could contribute to the development of chronic inflammation. METHODS: Immunohistological techniques were used to investigate the in vivo components of this particular fibroblast/T cell interaction in conjunctival biopsies from glaucoma patients undergoing filtration surgery. RESULTS: Fibroblast produced interferon beta and T lymphocytes were identified in human conjunctiva. CONCLUSION: The components of fibroblast mediated prevention of T cell apoptosis were identified in vivo, suggesting that the development of this interaction is possible and that it may contribute to the development of chronic inflammation and excessive scarring.

Aged↗
PubMed2001

Memory T cells constitute a subset of the human CD8+CD45RA+ pool with distinct phenotypic and migratory characteristics.

Using HLA class I-viral epitope tetramers to monitor herpes virus-specific CD8(+) T cell responses in humans, we have shown that a significant fraction of responding cells revert from a CD45RO(+) to a CD45RA(+) state after priming. All tetramer-binding CD45RA(+) cells, regardless of epitope specificity, expressed a phenotype LFA-1(high)CCR7(low) that was stable for at least 10 years in infectious mononucleosis patients and indefinitely in asymptomatic carriers. CD8(+)CD45RA(+)LFA-1(high) cells were not present in cord blood but in adults account for up to 50% of CD8(+)CD45RA(+) cells. These CD45RA(+)LFA-1(high) cells have significantly shorter telomeres than CD45RA(+)LFA-1(low) cells, suggesting that the latter represent a naive population, while the former are memory cells. CD45RA(+) memory cells are a stable population of noncycling cells, but on stimulation they are potent producers of IFN-gamma, while naive CD8(+) cells produce only IL-2. The chemokine receptor profile and migratory potential of CD45RA(+) memory cells is very similar to CD45RO(+) cells but different to naive CD8 cells. In accord with this, CD45RA(+) memory cells were significantly underrepresented in lymph nodes, but account for virtually all CD8(+)CD45RA(+) T cells in peripheral tissues of the same individuals.

Apoptosis↗
PubMed2001

The flow cytometric analysis of telomere length in antigen-specific CD8+ T cells during acute Epstein-Barr virus infection.

Acute infectious mononucleosis (AIM) induced by Epstein-Barr virus (EBV) infection is characterized by extensive expansion of antigen-specific CD8+ T cells. One potential consequence of this considerable proliferative activity is telomere shortening, which predisposes the EBV-specific cells to replicative senescence. To investigate this, a method was developed that enables the simultaneous identification of EBV specificity of the CD8+ T cells, using major histocompatibility complex (MHC) class I/peptide complexes, together with telomere length, which is determined by fluorescence in situ hybridization. Despite the considerable expansion, CD8+ EBV-specific T cells in patients with AIM maintain their telomere length relative to CD8+ T cells in normal individuals and relative to CD4+ T cells within the patients themselves and this is associated with the induction of the enzyme telomerase. In 4 patients who were studied up to 12 months after resolution of AIM, telomere lengths of EBV-specific CD8+ T cells were unchanged in 3 but shortened in one individual, who was studied only 5 months after initial onset of infection. Substantial telomere shortening in EBV-specific CD8+ T cells was observed in 3 patients who were studied between 15 months and 14 years after recovery from AIM. Thus, although telomerase activation may preserve the replicative potential of EBV-specific cells in AIM and after initial stages of disease resolution, the capacity of these cells to up-regulate this enzyme after restimulation by the persisting virus may dictate the extent of telomere maintenance in the memory CD8+ T-cell pool over time.

Acute Disease↗
PubMed2001

Human anergic/suppressive CD4(+)CD25(+) T cells: a highly differentiated and apoptosis-prone population.

Anergic/suppressive CD4(+)CD25(+) T cells exist in animal models but their presence has not yet been demonstrated in humans. We have identified and characterized a human CD4(+)CD25(+) T cell subset, which constitutes 7-10 % of CD4(+) T cells in peripheral blood and tonsil. These cells are a CD45RO(+)CD45RB(low) highly differentiated primed T cell population that is anergic to stimulation. Depletion of this small subset from CD4(+) T cells significantly enhances proliferation by threefold in the remaining CD4(+)CD25(-) T cells, while the addition of isolated CD4(+)CD25(+) T cells to CD4(+)CD25(-) T cells significantly inhibits proliferative activity. Blocking experiments suggest that suppression is not mediated via IL-4, IL-10 or TGF-beta and is cell-contact dependent. Isolated CD4(+)CD25(+) T cells are susceptible to apoptosis that is associated with low Bcl-2 expression, but this death can be prevented by IL-2 or fibroblast-secreted IFN-beta. However, the anergic/suppressive state of these cells is maintained after cytokine rescue. These human regulatory cells are therefore a naturally occurring, highly suppressive, apoptosis-prone population which are at a late stage of differentiation. Further studies into their role in normal and pathological situations in humans are clearly essential.

Apoptosis↗
PubMed2001

Fibroblasts regulate the switch from acute resolving to chronic persistent inflammation.

Fibroblasts are important sentinel cells in the immune system and, here, it is proposed that these cells play a critical role in the switch from acute inflammation to adaptive immunity and tissue repair. It is suggested that chronic inflammation occurs because of disordered fibroblast behaviour in which failure to switch off their inflammatory programme leads to the inappropriate survival and retention of leukocytes within inflamed tissue.

Acute-Phase Reaction↗
PubMed2001

Human tenon's fibroblast-produced ifnbeta and the prevention of t-cell apoptosis.

PURPOSE: Fibroblast-T-cell interactions may contribute to the development of chronic inflammation, a risk factor for trabeculectomy failure. This study was undertaken to determine whether normal and growth-arrested human Tenon's fibroblasts (HTF) can prevent cytokine deprivation-mediated T-cell apoptosis through the secretion of interferon (IFN)beta. METHODS: HTF were used either untreated or pretreated with mitomycin-C (MMC; 0.1 or 0.4 mg/ml) or 5-fluorouracil (5FU; 25 or 50 mg/ml). IL2-deprived T cells were cocultured with HTF. T-cell viability was measured at specific time points. Human Tenon's fibroblast-conditioned medium was used either untreated or treated with a neutralizing antibody against IFNbeta to block its action, after which IL2-deprived T cells were added and T-cell viability was measured. An image analysis system was used to determine the production of IFNbeta by either untreated or MMC-treated HTF. RESULTS: T-cell viability was significantly greater when T cells were cocultured with both untreated and growth-arrested HTF than when T cells were cultured alone (day 7, P = 0.0001). Neutralizing the action of IFNbeta blocked HTF-mediated T-cell rescue from apoptosis. Both untreated and growth-arrested HTF secrete IFNbeta, and MMC at 0.4 mg/ml appeared to increase IFNbeta production. CONCLUSIONS: Cytokine deprivation-mediated T-cell apoptosis can be prevented by the action of IFNbeta secreted by both normal and growth-arrested HTF, which suggests that growth-arrested HTF can still participate in an aggressive wound-healing reaction by mediating a persistent inflammatory phase. This may partly explain why some trabeculectomies fail in high-risk patients, despite the use of antimetabolites.

Apoptosis↗
PubMed2000

Differential regulation of CD8+ T cell senescence in mice and men.

The cytotoxic CD8+ T cell population expands considerably during acute immune infection with virus. Most of these cells are removed by apoptosis at the end of the immune response. However, a balance has to be attained between clearance and retention of a memory population of cells, which respond more rapidly and efficiently to secondary encounter with the antigen. In this article, the role of apoptosis and in particular the development of replicative senescence as mechanisms which control this homeostatic balance are discussed. Although similar mechanisms regulate apoptosis in both humans and rodents, the available data suggests that replicative senescence may be controlled differently in these species, suggesting the there may be different constraints in the regulation of CD8+ T cell memory between different species.

Acute Disease↗
PubMed2000

Type 1 IFN maintains the survival of anergic CD4+ T cells.

Anergic T cells have immunoregulatory activity and can survive for extended periods in vivo. It is unclear how anergic T cells escape from deletion, because both anergy and apoptosis can occur after TCR ligation. Stimulation of human CD4+ T cell clones reactive to influenza hemagglutinin peptides can occur in the absence of APCs when MHC class II-expressing, activated T cells present peptide to each other. This T:T peptide presentation can induce CD95-mediated apoptosis, while the cells that do not die are anergic. We found that the death after peptide or anti-CD3 treatment of a panel of CD4+ T cell clones is blocked by IFN-beta secreted by fibroblasts and also by IFN-alpha. This increases cell recovery after stimulation, which is not due to T cell proliferation. This mechanism for apoptosis inhibition rapidly stops protein kinase C-delta translocation from the cytoplasm to the nucleus, which is an early event in the death process. A central observation was that CD4+ T cells that are rescued from apoptosis after T:T presentation of peptide by IFN-alphabeta remain profoundly anergic to rechallenge with Ag-pulsed APCs. However, anergized cells retain the ability to respond to IL-2, showing that they are nonresponsive but functional. The prevention of peptide-induced apoptosis in activated T cells by IFN-alphabeta is a novel mechanism that may enable the survival and maintenance of anergic T cell populations after TCR engagement. This has important implications for the persistence of anergic T cells with the potential for immunoregulatory function in vivo.

Antigen-Presenting Cells↗
PubMed2000

Follicular dendritic cells share a membrane-bound protein with fibroblasts.

The expression of a fibroblast antigen (AS02) on a proportion of CD21+ follicular dendritic cells (FDCs) provides evidence in support of their fibroblastic reticular origin. This antigen is expressed on the membrane of tissue fibroblasts but is absent from lymphocytes, macrophages or granulocytes. The distribution of AS02 in conjunction with other FDC markers (DRC-1, RFD3, CD23, IgM, and vitronectin) showed six types of FDCs. AS02 is present in the outer layers of primary and secondary follicles, but gradually decreases and disappears in the centre of germinal centres. In contrast, there is a progressive up-regulation of the other FDC markers. AS02 is re-expressed in involuting FDCs. Intermediate forms from fibroblastic to dendritic appearance are also apparent and occasionally FDC processes contain collagen type I and IV fibres, a characteristic feature of fibroblasts. In pathological follicles the normal differentiation pattern is disrupted, with persistence of the fibroblast marker, possibly due to altered interactions between FDCs and disrupted lymphocytic patterns. These findings provide new evidence for a local differentiation pathway of fibroblasts to mature FDCs.

Arthritis, Rheumatoid↗
PubMed2000

IFN-alpha and IFN-beta: a link between immune memory and chronic inflammation.

The majority of expanded T cells generated during an immune response are cleared by apoptosis. Prevention of death in some activated T cells enables the persistence of a memory T-cell pool. Here, observations that IFN-alpha and IFN-beta inhibit activated T-cell apoptosis are described. Although this enables memory T cells to persist without antigen, excessive IFN-alpha or IFN-gamma secretion might lead to chronic inflammation.

Animals↗
PubMed2000

Regulation of apoptosis and replicative senescence in CD8+ T cell following acute viral infection.

Viral infections are characterised by a large expansion of CD8+ effector T cells. Once generated, these T cells must be cleared and homeostasis re-established. In this review we describe two mechanisms, apoptosis and replicative senescence which are thought to play a vital role in this process. Apoptosis clears the unwanted T cells at the end of an immune response whereas replicative senescence prevents unlimited expansion of T cells. For successful memory to be produced T cells must avoid apoptosis and avoid replicative senescence.

Animals↗
PubMed2000

Regulation of apoptosis and replicative senescence in CD8+ T cells from patients with viral infections.

Activated T lymphocytes are generated during an immune response. The induction of T lymphocyte proliferation is one way in which cell numbers can be controlled. However, once generated, the increased numbers of cells must be removed in order to re-establish cellular homoeostasis within the immune system. In this paper we describe how the numbers of activated T cells can be regulated by two distinct mechanisms, namely apoptosis and replicative senescence. In addition, we suggest that the regulation of cell clearance, as opposed to cell persistence, after an immune response is intimately involved in the generation of immune memory.

Apoptosis↗
PubMed2000

The inhibition of cutaneous T cell apoptosis may prevent resolution of inflammation in atopic eczema.

Atopic eczema (AE) is characterized by the persistence of infiltrating T lymphocytes in the dermis. To test the hypothesis that dysregulation of normal T cell apoptosis may contribute to the pathogenesis and chronicity of AE we compared patients with a normal resolving immune response (Mantoux reaction (MR)) induced in healthy volunteers by cutaneous PPD injection. Significantly less T cell apoptosis was observed in lesional skin of AE patients compared with either the peak or the resolution phase of the MR (P < 0.0001). The low incidence of T cell apoptosis in AE was associated with significantly increased levels of Bcl-2 relative to Bax (P < 0.0001) and significantly decreased CD95-L expression (P < 0.002) compared with the resolving MR. The cytokines IL-15 and interferon-beta (IFN-beta), which prevent activated T cell apoptosis, were expressed maximally on day 7 and day 14 of the MR, respectively. In contrast, AE patients expressed high levels of both IL-15 and IFN-beta in cutaneous lesions at the same time. This suggests that the co-expression of two anti-apoptotic cytokines, which are not found together during resolving cutaneous responses, may contribute to excessive T cell survival which leads to the persistence of inflammation in patients with AE.

Adolescent↗