Current post- onset treatments are either substitutive (e. Tregs), or combinations thereof. A. Antigen- Specific Intervention Trials in T1. DIn general, the idea behind antigen- based therapies is to induce Treg responses (active tolerance) or anergizing/deleting pathogenic T cells (passive tolerance) without having the side effects of long- term immune suppression. Tolerizing against insulin or GAD6. Regulatory T cells and type 1 diabetes. A summary of the changes in T cells. Basic Concepts of T and B Cells in Immunity. T and B cells are the main. 22 Although diet and plasma cholesterol. This approach has also led to success in T1. D patients (8. 7, 1. Table 3). Future trials should also target other peptides (1. Table 3. Intervention trials and Ag- specific monotherapy. Several clinical intervention trials target insulin, because it is the initiating antigen in the NOD model and it is also a major autoantigen in human T1. D. A phase I trial has confirmed the data in animal models that incomplete Freund's adjuvant (IFA)- enhanced human insulin B- chain vaccination is safe and can induce insulin- specific Tregs for up to 2 years after vaccination (2. A follow- up trial will determine the effects on glycemic control (3. Another approach uses a Cp. G- free proinsulin- based DNA plasmid vaccine BHT- 3. Bayhill Therapeutics). This vaccine is designed to tolerize the immune system to proinsulin by combining DNA codons for an immunodominant peptide of insulin (4. Cp. G oligonucleotides (1. Striking data in recent- onset diabetic NOD mice suggested that BHT- 3. Tregs (4. 40) that can act as bystander suppressors. In recent- onset patients, the vaccine can preserve C- peptide and reduce Hb. A1c (1. 62). This demonstrates the increased efficacy of the Bay. Hill plasmid compared with the first generation of insulin B- expressing p. Regulatory T-cell immunity and its relevance to atherosclerosis. Effector T cells recognize modified auto. Review Article Shaping the (auto)immune response in the. Keywords: Intestinal immunity, microbiota, diet, dendritic cells, regulatory T cells. Wold, Agnes E., Hultkrantz, S. Systemic impact of intestinal helminth infections. CMV plasmids (9. 4). Another target for antigen- specific therapy is GAD6. GAD- Alum is an aluminum hydroxide (Alum) formulation of full- length recombinant human GAD6. Diamyd Therapeutics). It was shown to be safe and to preserve residual insulin secretion in subjects with late- onset autoimmune diabetes of adulthood (LADA) (7). A subsequent phase II trial in recent- onset T1. D showed significant preservation of residual insulin secretion and a GAD- specific immune response, both humoral and cell mediated (8). Currently, phase III studies are ongoing in Europe and the United States. The patients in all these trials were selected on the basis of elevated GAD6. The formulation is crucial to Dyamid's GAD drug because 1) adjuvant reduces the required quantity of antigen and 2) aluminum salts preferentially induce a humoral rather than cellular immune response (2. Immune readouts show an increase in Fox. P3 and transforming growth factor- . Combination therapies with a short- term course of a suitable immune modulator are considered to enhance efficacy in recent- onset patients. B. Non- antigen- Specific Intervention Trials in T1. DSince autoimmunity is the main effector mechanism in T1. D, many intervention trials have used drug regimens to silence and/or modulate the immune response, preferably without negative effects on Tregs (Table 4). These immune- suppressive regimens will also prove valuable, if not critical, for the success of islet transplants and/or . Cyclosporine A inhibits calcineurin, which is responsible for the activation of IL- 2 transcription. The lack of IL- 2 and other cytokines reduces the function of effector T cells, but unfortunately also of Tregs. Cyclosporine treatment induced remission of T1. D, but its chronic use was suspended because of unacceptable side effects (2. However, this limited success indicated that immunosuppression can reduce the autoimmune inflammation in T1. D. Dia. Pep. 27. 7 was originally used in an antigen- specific therapy. The idea was that this peptide from HSP6. T1. D because of cross- reactivity (1. More recent insights indicate that Diap. HSP6. 0 induces Treg via the Toll- like receptor (TLR)- 2 (4. A phase II trial showed that Dia. Pep. 27. 7 preserved C- peptide up to 1. T1. D patients (3. Beta- cell preservation was associated with IL- 1. T- cell proliferation after treatment (2. But so far, no Dia. Pep. 27. 7- specific Tregs have been characterized in mice or humans. However, while a phase III study is ongoing in adults, no treatment effect was observed in children with T1. D (2. 40). An important class of biological immune modulators comprises antibodies that target receptors on T cells. For example, Fc. R- non- binding anti- CD3 monoclonal antibodies (m. Abs) have shown the most promising results so far in T1. D therapy. Anti- CD3 m. Ab acts at various levels. It causes a short- term internalization of the TCR- CD3 complex that makes the cell “blind” to antigen (8. Also, it alters TCR- mediated signal transduction so that anergy or apoptosis is induced preferentially in activated Th. The apoptosis is partially mediated by CD9. CD9. 5L interactions with neighboring T cells. This might explain why effector T- cell death is most dramatic where the T- cell density is highest, i. Moreover, anti- CD3 treatment also results in Treg development (4. It is thought that the Tregs may protect against damage by effector T cells long after the drug has been eliminated from the body. To obtain all these effects, optimal dosage is crucial. Too little m. Ab causes insufficient modulation and Treg generation, whereas too much m. Ab could lead to stimulation of the effector T cells and cytokine release. Multiple clinical trials have been initiated and were based on two different antibodies, both fully humanized Ig. G1, nonmitogenic and specific to human CD3 (Table 4): Teplizumab (United States trials) and TRX4/Otelixizumab (European trials) (5. Teplizumab halted progression of recent- onset T1. D for more than 1 year in most patients (phase II). Three years after treatment, the patients continued to have better preservation of C- peptide levels and a lower use of insulin compared with control groups (1. TRX4/Otelixizumab also preserved beta- cell function very efficiently and decreased the insulin requirements drastically, even 1. However, none of these treatments achieved euglycemia. The European study also revealed two side effects. First, anti- idiotypic antibodies were detected 2–3 wk after injection of the drug. This should only become a problem when repeated treatment is needed. Second, there was reactivation of Epstein- Barr virus, but this was transient, self- limiting, and isolated (2. Other approaches using polyclonal anti- T cell antibody (ALS) (3. ATG) might be able to temporarily eliminate a larger proportion of T cells from the bloodstream. In NOD mice, murine ATG can prevent diabetes in a late stage and can induce Tregs (3. It is unclear whether ATG will be as efficient as anti- CD3 (3. Treatment of T1. D patients with r. ATG (ATG- Fresenius) prolonged the honeymoon period and improved the stimulated C- peptide levels up to 1. Consequently, ATG monotherapy is now tested in a phase II trial, the Study of Thymoglobulin to Arrest T1. D (START). But ATG treatment also carries risks. ATG can cause cytokine release syndrome and maybe even a lymphopenia- induced outgrowth of autoreactive T cells, as was shown for other depletion- based immunosuppression (2. Combination treatment with equine ATG and prednisone, a steroid that can counteract the cytokine release syndrome, led to a prolonged honeymoon phase in new- onset T1. D (1. 25). But most promising in the ATG trials was that some subjects went into complete remission and were insulin independent for at least 1 mo. An immunomodulatory drug adopted from the transplantation arena is the CD2. Ab rituximab (Rituxan; Genentech and Biogen Idec). Rituximab aims to deplete a potentially potent antigen- presenting population of B cells without affecting long- lived antibody- producing plasma cells (1. Data from NOD mice clearly show that B cells are required for T1. D (3. 88). A phase II clinical trial showed some preservation of C- peptide levels for 3–6 mo (3. B cells also contribute to pathogenesis in human T1. D. However, the efficacy is small compared with anti- CD3 treatments (1. Perhaps Ocrelizumab, a humanized anti- CD2. RA (1. 54), might increase efficacy of B- cell depletion in T1. D. Anti- CD2. 5 m. Abs such as basiliximab (chimeric mouse- human monoclonal antibody) and daclizumab (humanized Ig. G1 m. Ab) do not cause a cytokine release syndrome. Therefore, they are increasingly being used in place of ATG as an induction therapy. However, in T1. D, anti- CD2. Abs are only used in combination therapies (see below). Another class of targets consists of costimulatory molecules. CTLA- 4- Ig (Abatacept), CTLA- 4 fused to an immunoglobulin chain, interferes with costimulation of T cells. Classically, CD2. B7 interactions mediate costimulation and significantly enhance peripheral T- cell responses. In contrast, CTLA- 4, interacting with the same B7 molecules, dampens T- cell activity. So, CTLA- 4- Ig likely mediates its profound effects by preventing positive costimulation of CD2. B7 during activation. This results in limited clonal expansion, induction of passive cell death, and IDO production in APCs (reviewed in Refs. The safety profile of CTLA- 4- Ig treatment might be better than other immunosuppressive agents, because CTLA- 4- Ig does not deplete T cells. However, because of the role of CD2. Treg development and survival (3. CTLA- 4- Ig may negatively affect Tregs. That said, CTLA- 4- Ig therapy did not affect Tregs in renal transplantation (1. CTLA- 4- Ig monotherapy is currently in a phase II clinical trial (data not published). Moreover, a high- affinity variant of CTLA4- Ig (LEA2. Y, belatacept) (2. I/II trial (NCT0. And the LEA2. 9Y Emory Edmonton Protocol (LEEP, NCT0. II clinical trial combines CTLA- 4- Ig with daclizumab or basiliximab (against acute transplant rejection) and mycophenolate mofetil (maintenance immunosuppressive therapy). Manipulation of cytokines has seen a revival recently. Both the cytokines that affect T- cell responses (e. IL- 2, IL- 1. 5) and the cytokines that play a role in inflammation and beta- cell death are considered as targets.
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