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Biomedical subjects

Elizabeth Adams

Publications and source records attributed to Elizabeth Adams.

At least 19 recordsLinked to original sources
PubMed2006

Regulatory T cells in transplantation.

Our ability to harness tolerance mechanisms will have a major impact in organ transplantation. It should enable drug minimization, and eventually, the elimination of all immunosuppressive drugs. An improved understanding of the biology of regulatory T cells will make it possible to replace current induction regimens with those favouring the selective vaccination of T cells that prevent graft rejection. Once regulation is established, the continued supply of graft antigens should empower T cell regulation to become the dominant natural mechanism to prevent graft rejection.

Animals↗
PubMed2006

Infectious tolerance and the long-term acceptance of transplanted tissue.

Short courses of antibody treatment aimed at blocking the coreceptors CD4 and CD8 and/or costimulatory molecules such as CD40L are able to bring about long-term acceptance and tolerance of allogeneic transplants. This tolerant state is operational, in that potential effector cells remain but are tightly regulated through the induction of antigen-specific CD4+ regulatory T cells (Tregs). CD4+ CD25+ FoxP3+ Tregs appear to play a prominent role, although other categories of Tregs have been documented. Transforming growth factor beta (TGFbeta) has been found to play a major role in the induction of the tolerant state with therapeutic antibodies as well as promoting the induction of FoxP3+ T cells from naïve populations. The observation that Tregs can be found in tolerated grafts has led to the idea that they may interact with the grafted tissue to establish a state of acquired privilege symmetrical with a similar privileged microenvironment around antigen-presenting cells in lymphoid tissues. Dampening of aggressive immune responses by Tregs allows antigen to persist and be presented in an innocuous way to promote tolerance in new cohorts of T cells throughout the life of the tolerated graft. Regulation may operate at many stages of an immune response, even as a censor at the terminal differentiation stages of effector function.

Animals↗
PubMed2006

Immune privilege induced by regulatory T cells in transplantation tolerance.

Immune privilege was originally believed to be associated with particular organs, such as the testes, brain, the anterior chamber of the eye, and the placenta, which need to be protected from any excessive inflammatory activity. It is now becoming clear, however, that immune privilege can be acquired locally in many different tissues in response to inflammation, but particularly due to the action of regulatory T cells (Tregs) induced by the deliberate therapeutic manipulation of the immune system toward tolerance. In this review, we consider the interplay between Tregs, dendritic cells, and the graft itself and the resulting local protective mechanisms that are coordinated to maintain the tolerant state. We discuss how both anti-inflammatory cytokines and negative costimulatory interactions can elicit a number of interrelated mechanisms to regulate both T-cell and antigen-presenting cell activity, for example, by catabolism of the amino acids tryptophan and arginine and the induction of hemoxygenase and carbon monoxide. The induction of local immune privilege has implications for the design of therapeutic regimens and the monitoring of the tolerant status of patients being weaned off immunosuppression.

Animals↗
PubMed2006

Impact of varying levels of protein intake on protein status indicators after gastric bypass in patients with multiple complications requiring nutritional support.

BACKGROUND: <6% of patients who undergo Roux-en-Y gastric bypass (RYGBP) for morbid obesity require nutritional support after surgery. Protein and caloric needs have been estimated as 14-21 kcal, 1.2 g protein/kg/current body weight/day in uncomplicated morbidly obese patients. This study assesses the effect of varying protein-calorie intake in complicated patients after RYGBP on two markers of protein status: thyroxine-binding prealbumin (TBPA) and serum albumin. METHODS: This 25-month retrospective study consisted of 22 patients with postoperative complications. Serum albumin, TBPA, medical nutrition care-plans, laboratory data and history were reviewed. These post-RYGBP patients who had BMI>35 and no multi-system organ failure or fistulas, had complications after surgery requiring nutrition support services (NSS). Serum albumin and TBPA were matched to fed levels of protein using random coefficient regression analysis. RESULTS: Mean incremental increases of 2.34 mg/dl (TBPA, P=0.0113) and 0.11 g/dl (serum albumin, P=0.0272) were found with each 0.5 g protein intake increase/kg ideal body weight/day (kg/IBW/day). Patients required NSS for 23+/-21 (mean+/-SD) days, with 15+/-19 days fed at goal rate. Initial serum albumin was 2.3+/-0.5, with a final measure of 2.7+/-0.5 g/dl. Goal protein and calorie intake were 2.1 g and 17 kcal/kg IBW/day versus actual intake of 1.6 g and 13 kcal/kg IBW/day. CONCLUSION: Morbidly obese patients requiring NSS following RYGBP risk iatrogenic protein malnutrition. There was a positive linear relationship between protein status and protein intake that warrants further study of higher protein feeding in complicated post-RYGBP patients.

Adult↗
PubMed2005

Leukemia inhibitory factor is linked to regulatory transplantation tolerance.

BACKGROUND: The specific regulation of allo-tolerance in vivo occurs within a complex microenvironment and involves co-operation between a small proportion of different cell types within the spleen or draining lymph node. By analyzing unmanipulated whole spleen cell populations we have aimed to mimic this in vivo situation to identify critical signaling molecules in regulatory allo-tolerance. METHODS: We compared the kinetics of cytokine release and induction of signaling proteins in (BALB/c-tolerant)CBA, versus (BALB/c-rejected)CBA, spleen cells after challenge with BALB/c antigen. RESULTS: The distinguishing features of allo-tolerance were Foxp3 protein expression, LIF release, and increased levels of STAT3. Comparison of isogenic clones of Tr1, Th1, and Th2 cells revealed that only the regulatory Tr1 cells are characterized by both LIF and IL10 release. CONCLUSIONS: Overall, our findings demonstrate that allo-antigen driven signaling events can be detected within a whole spleen cell population and identify a role for LIF in the regulation of transplantation tolerance in vivo.

Animals↗
PubMed2005

Hepatitis B virus replication in damaged endothelial tissues of patients with extrahepatic disease.

Hepatitis B virus (HBV) infection may be complicated by extrahepatic manifestations such as polyarteritis nodosa (PAN), glomerulonephritis, polymyositis, and dermatitis, but the etiology of these processes is not yet clear. HBV replication has been demonstrated in a variety of extrahepatic tissues and cell types, but the possible pathogenetic role of extrahepatic HBV replication has not been fully explored in patients with extrahepatic manifestations of HBV infection. In this case series, immunohistochemistry and in situ hybridization studies were performed on extrahepatic tissues from one HBsAg-positive patient with PAN and another HBsAg-positive patient with polymyositis, using HBsAg-seronegative control subjects with the same vasculitic disorders as controls. Tissue samples from the two study patients had detectable HBV RNA, replicative intermediates of HBV DNA, as well as HBsAg and HBcAg localized to vascular endothelium. In contrast, HBsAg-negative control patients had no tissue reactivity. Our results suggest that patients with HBV-related extrahepatic disease have evidence of viral replication in damaged extrahepatic endothelial tissues. While further studies would be required to support a hypothesis of causality, these findings suggest a role for both immune complex deposition and viral replication within diseased endothelial tissue in the pathogenesis of these poorly understood extrahepatic disorders.

Adult↗
PubMed2005

Amprenavir and efavirenz pharmacokinetics before and after the addition of nelfinavir, indinavir, ritonavir, or saquinavir in seronegative individuals.

Adult AIDS Clinical Trials Group 5043 examined pharmacokinetic (PK) interactions between amprenavir (APV) and efavirenz (EFV) both by themselves and when nelfinavir (NFV), indinavir (IDV), ritonavir (RTV), or saquinavir (SQV) is added. A PK study was conducted after the administration of single doses of APV (day 0). Subjects (n = 56) received 600 mg of EFV every 24 h (q24h) for 10 days and restarted APV with EFV for days 11 to 13 with a PK study on day 14. A second protease inhibitor (PI) (NFV, 1,250 mg, q12h; IDV, 1,200 mg, q12h; RTV, 100 mg, q12h; or SQV, 1,600 mg, q12h) was added to APV and EFV on day 15, and a PK study was conducted on day 21. Controls continued APV and EFV without a second PI. Among subjects, the APV areas under the curve (AUCs) on days 0, 14, and 21 were compared using the Wilcoxon signed-rank test. Ninety-percent confidence intervals around the geometric mean ratios (GMR) were calculated. APV AUCs were 46% to 61% lower (median percentage of AUC) with EFV (day 14 versus day 0; P values of <0.05). In the NFV, IDV, and RTV groups, day 21 APV AUCs with EFV were higher than AUCs for EFV alone. Ninety-percent confidence intervals around the GMR were 3.5 to 5.3 for NFV (P < 0.001), 2.8 to 4.5 for IDV (P < 0.001), and 7.8 to 11.5 for RTV (P = 0.004). Saquinavir modestly increased the APV AUCs (GMR, 1.0 to 1.4; P = 0.106). Control group AUCs were lower on day 21 compared to those on day 14 (GMR, 0.7 to 1.0; P = 0.042). African-American non-Hispanics had higher day 14 efavirenz AUCs than white non-Hispanics. We conclude that EFV lowered APV AUCs, but nelfinavir, indinavir, or ritonavir compensated for EFV induction.

Adolescent↗
PubMed2004

Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase.

Murine dendritic cells (DCs) expressing indoleamine 2,3 dioxygenase (IDO) catabolize tryptophan and can suppress T cell responses elicited in vivo. Here, we identify specific subsets of splenic (CD11c+) dendritic cells competent to mediate IDO-dependent T cell suppression following CTLA4-mediated ligation of B7 molecules. IDO-competent DC subsets acquired potent and dominant T cell suppressive properties as a consequence of IDO up-regulation, as they blocked the ability of T cells to respond to other stimulatory DCs in the same cultures. Soluble CTLA4 (CTLA4-Ig) and cloned CTLA4+ regulatory T cells (Tr1D1) up-regulated IDO selectively in DC subsets co-expressing B220 or CD8alpha. The ability of Tr1D1 T cells to suppress CD8+ T cell responses was completely dependent on their ability to induce tryptophan catabolism in DCs. Selective IDO up-regulation in DCs did not inhibit T cell activation, but prevented T cell clonal expansion due to rapid death of activated T cells. T cell responses were restored by genetic or pharmacologic inhibition of IDO enzyme activity, or by adding excess tryptophan. DCs from interferon gamma (IFNgamma)-receptor-deficient mice were effective in promoting IDO-dependent T cell suppression following CTLA4-Ig exposure in vivo, indicating that IFNgamma signaling was not necessary for IDO up-regulation in this model. These findings suggest that IDO-competent DCs provide a regulatory bridge, mediated by CTLA4-B7 engagement, between certain regulatory T cell subsets and naive responder T cells.

Abatacept↗
PubMed2004

Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants.

Transplantation tolerance can be induced in mice by grafting under the cover of nondepleting CD4 plus CD8 or CD154 mAbs. This tolerance is donor Ag specific and depends on a population of CD4(+) regulatory T cells that, as yet, remain poorly defined in terms of their specificity, origin, and phenotype. Blocking of the Ag-specific response in vitro with an anti-CD4 mAb allowed T cells from monospecific female TCR-transgenic mice against the male Ag Dby, presented by H-2E(k), to express high levels of foxP3 mRNA. foxP3 induction was dependent on TGF-beta. The nondepleting anti-CD4 mAb was also able to induce tolerance in vivo in such monospecific TCR-transgenic mice, and this too was dependent on TGF-beta. As in conventional mice, acquired tolerance was dominant, such that naive monospecific T cells were not able to override tolerance. Splenic T cells from tolerant mice proliferated normally in response to Ag, and secreted IFN-gamma and some IL-4, similar to control mice undergoing primary or secondary graft rejection. High levels of foxP3 mRNA, and glucocorticoid-induced TNFR superfamily member 18 (GITR)(+) CD25(+) T cells were found within the tolerated skin grafts of long-term tolerant recipients. These data suggest that regulatory T cells maintaining transplantation tolerance after CD4 Ab blockade can be induced de novo through a TGF-beta-dependent mechanism, and come to accumulate in tolerated grafts.

Amino Acid Sequence↗
PubMed2004

Regulatory T cells and organ transplantation.

Empirical studies attempting to explain tolerance to transplanted tissues have demonstrated a regulatory role for CD4+ T-cells. We here propose that regulatory T-cells mediating transplantion tolerance comprise two sets which can functionally complement each other. The CD4+CD25+ "natural regulator" arises in the thymus, and is preoccupied with self-antigens expressed at sites of inflammation. The second, comprising both CD4+CD25+ (FoxP3+) and CD4+CD25- Tr1-like cells are induced by persistent danger-free antigen in the periphery. The role of these cells is to moderate immune responses to prevent tissue destruction while allowing microbial elimination.

Animals↗
PubMed2003

Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells.

Recently, agonist antibodies to glucocorticoid-induced tumor necrosis factor receptor (GITR) (tumor necrosis factor receptor superfamily 18) have been shown to neutralize the suppressive activity of CD4+CD25+ regulatory T cells. It was anticipated that this would be the role of the physiological ligand. We have identified and expressed the gene for mouse GITR ligand and have confirmed that its interaction with GITR reverses suppression by CD4+CD25+ T cells. It also, however, provides a costimulatory signal for the antigen-driven proliferation of naïve T cells and polarized T helper 1 and T helper 2 clones. RT-PCR and mAb staining revealed mouse GITR ligand expression in dendritic cells, macrophages, and B cells. Expression was controlled by the transcription factor NF-1 and potentially by alternative splicing of mRNA destabilization sequences.

Alternative Splicing↗
PubMed2003

Regulatory T cells in the induction and maintenance of peripheral transplantation tolerance.

It is now possible to induce donor-specific transplantation tolerance in adult rodents using non-depleting monoclonal antibodies against T cell co-receptor and co-stimulation molecules or by immunisation with tolerogenic antigen-presenting cells. It is a common finding of all these models of peripheral tolerance, as well as of various mouse models of autoimmune disease, that regulatory CD4(+) T cells are the principal mediators. There are currently no specific markers for regulatory T cells, but in some autoimmune models their activity has been associated with the expression of activation markers such as CD25 and CTLA4, or anti-inflammatory cytokines such as IL-10 and TGF-beta. CD4(+)CD25(+) T cells from both naïve and tolerised donors are able to transfer tolerance to grafts in lymphopenic recipients, and this may be directly applicable to bone-marrow transplantation. The challenge is now to understand the biological principles that allow such immune re-programming so that they can be safely applied to clinical organ grafting.

Animals↗
PubMed2003

Serial analysis of gene expression provides new insights into regulatory T cells.

It is now possible to induce donor-specific transplantation tolerance in adult rodents using a number of therapeutic strategies. Such peripheral tolerance is maintained by regulatory CD4+ T cells, not only in transplantation models, but also in autoimmunity. Differential gene expression analyses have been used to identify potential new markers for regulatory T cells, aiming to reveal new insights into their mechanisms of action, and to find novel targets for therapeutic manipulation of the immune system.

Animals↗
PubMed2003

Regulatory T cells and dendritic cells in transplantation tolerance: molecular markers and mechanisms.

Transplantation tolerance can be induced in adult rodents using monoclonal antibodies against coreceptor or costimulation molecules on the surface of T cells. There are currently two well-characterized populations of T cells, demonstrating regulatory capacity: the "natural" CD4+CD25+ T cells and the interleukin (IL)-10-producing Tr1 cells. Although both types of regulatory T cells can induce transplantation tolerance under appropriate conditions, it is not clear whether either one plays any role in drug-induced dominant tolerance, primarily due to a lack of clear-cut molecular or functional markers. Similarly, although dendritic cells (DCs) can be pharmacologically manipulated to promote tolerance, the phenotype of such populations remains poorly defined. We have used serial analysis of gene expression (SAGE) with 29 different T-cell and antigen-presenting cell libraries to identify gene-expression signatures associated with immune regulation. We found that independently derived, regulatory Tr1-like clones were highly concordant in their patterns of gene expression but were quite distinct from CD4+CD25+ regulatory T cells from the spleen. DCs that were treated with the tolerance-enhancing agents IL-10 or vitamin D3 expressed a gene signature reflecting a functional specification in common with the most immature DCs derived from embryonic stem cells.

Animals↗
PubMed2002

Both CD4(+)CD25(+) and CD4(+)CD25(-) regulatory cells mediate dominant transplantation tolerance.

CD4(+)CD25(+) T cells have been proposed as the principal regulators of both self-tolerance and transplantation tolerance. Although CD4(+)CD25(+) T cells do have a suppressive role in transplantation tolerance, so do CD4(+)CD25(-) T cells, although 10-fold less potent. Abs to CTLA-4, CD25, IL-10, and IL-4 were unable to abrogate suppression mediated by tolerant spleen cells so excluding any of these molecules as critical agents of suppression. CD4(+)CD25(+) T cells from naive mice can also prevent rejection despite the lack of any previous experience of donor alloantigens. However, this requires many more naive than tolerized cells to provide the same degree of suppression. This suggests that a capacity to regulate transplant rejection pre-exists in naive mice, and may be amplified in "tolerized" mice. Serial analysis of gene expression confirmed that cells sorted into CD4(+)CD25(+) and CD4(+)CD25(-) populations were distinct in that they responded to TCR ligation with very different programs of gene expression. Further characterization of the differentially expressed genes may lead to the development of diagnostic tests to monitor the tolerant state.

Abatacept↗
PubMed2002

Regulatory T cells overexpress a subset of Th2 gene transcripts.

There is now compelling evidence for subpopulations of CD4+ T cells whose role is to prevent immune pathology in both autoimmunity and transplantation. We have cloned CD4+ T cells against a male transplantation Ag that, unlike Th1 or Th2 clones, suppresses the rejection of male skin grafts and are therefore considered examples of regulatory T cells. We have identified, using serial analysis of gene expression, transcripts that are overexpressed in regulatory T cells compared with Th1 and Th2 clones. Some of these transcripts are increased in tolerated rather than rejecting skin grafts and in addition are expressed by the natural regulatory CD4+CD25+ subpopulation of naive mice. These genes include prepro-enkephalin, GM2 ganglioside activator protein, glucocorticoid-induced TNFR superfamily member 18, and integrin alpha(E)beta(7). They seem to represent a subset of transcripts shared with Th2 cells, suggesting that transplantation tolerance and normal immunoregulation may represent a unique form of Th2-like differentiation.

Adoptive Transfer↗