Few note on recent news about APL and IDDM.
APL and IDDM is approach which will need years to complete clinical trials. If APL for MS has good results so far (after first PII, at least Novartis is continuing with clinical development), why is none interested to partner this program from NBIX????
From the DPT-1 trial, and related to pts screen before they are enrolled. Today it is possible to fine tune pts population at very early childhood IDDM onset, so NBIX approach do make a loot sense, if drug is effective.
<<Today there are blood tests which help us predict just who will develop IDDM and when:
Islet Cell Autoantibodies (ICAs): This is a blood test that measures the levels of antibodies against islet cells long before the onset of IDDM. Close relatives of a person with IDDM who test positive for ICAs are much more likely to develop IDDM than are relatives who test negative. The DPT-1 will use this as a screening test to determine if you are eligible for further testing.
Insulin Autoantibodies (IAAs): This blood test measures antibodies produced by the body against its own insulin. When associated with ICA, these signify an increased risk of developing IDDM.
First-Phase Insulin Release (FPIR): This is a more sophisticated blood test performed by an intravenous glucose tolerance test (IVGTT). This test measures the degree of beta cell damage that has already occurred.
Taken together, information from these three tests allow researchers to estimate a person's relative risk of developing IDDM within the next five years. (NOTE: All blood tests are free to you.)>>
However, I was not able to identify single info which will lead to NBIX islet cell antigen info or APL peptide size and any preclinical data. NBIX initiate in 97 collaboration with BDC at UofC (for preclinical studies). BDC homepage:
uchsc.edu
Few abstracts from Medline which deal with APL and IDDM:
J Autoimmun 1998 Aug;11(4):353-61
Altered peptide ligands of islet autoantigen Imogen 38 inhibit antigen specific T cell reactivity in human type-1 diabetes.
Geluk A, van Meijgaarden KE, Roep BO, Ottenhoff TH
Department of Immunohematology and Blood Bank, Leiden University Medical Center, The Netherlands. Geluk@rullf2.Medfac.Leidenuniv.nl
Type 1 diabetes, insulin-dependent diabetes mellitus (IDDM) results from autoimmune T cell-dependent destruction of insulin producing beta-cells in the pancreatic islets of Langerhans. T cells from recent-onset IDDM patients specifically proliferate to beta cell membrane Ag enriched fractions, containing the mitochondrial 38 kD islet antigen (Imogen). Recently, we identified a peptide epitope (Imogen p55-70) that is recognized by a 38 kD-specific, Th1 clone from an IDDM patient. In animal models of autoimmune diseases, altered self peptide ligands (APL) have been used effectively in peptide-based immune prevention or therapy. No such APL, however, have been reported so far that can modulate autoreactive T-cell responses in IDDM. Here, we have designed APL of p55-70. These APL efficiently downregulate in vitro activation of the 38 kD-specific Th1 clone induced by either p55-70 or by native beta cell autoantigens. Self peptide reactive T-cell proliferation could be inhibited only when APL and the self peptide were present on the same APC. Unrelated peptides with equal HLA-DR binding affinity were not effective, excluding simple MHC competition as the mechanism for T-cell modulation. APL triggered upregulation of CD69 and CD25 expression, but not T-cell proliferation, TCR down-modulation or T-cell anergy. Thus, the p55-70 APL inhibit beta cell autoantigen-induced activation of an Imogen-reactive T-cell clone derived from an IDDM patient, by acting as partial TCR agonists that inhibit TCR down-modulation. Copyright 1998 Academic Press
Crit Rev Immunol 1997;17(5-6):519-28
Modulation of insulin-dependent diabetes mellitus (IDDM) in NOD mice by autoreactive T cells.
Chaturvedi P, Qin HY, Chou H, Singh B
Department of Microbiology and Immunology, University of Western Ontario, London, Canada.
Insulin-dependent diabetes mellitus (IDDM) is a T-cell-mediated autoimmune disease characterized by the destruction of insulin-producing beta cells in the islet of Langerhans. Islet autoantigen-specific T cells play a major role in the pathogenesis of the disease. Susceptibility loci for autoimmune diabetes such as the major histocompatability complex (MHC) may function by producing different repertoires of T cells, which could gain autoreactivity following activation, resulting in autoimmune disease. However, all the T cells infiltrating the islets are not destructive. A number of autoreactive T-cell lines capable of preventing development of IDDM have been isolated. Most of these cell lines are reactive to self I-Ag7. Presence of these regulatory T cells along with the effector cells in nonobese diabetic (NOD) mice suggests that IDDM may be a result of the imbalance of these two types of cells. Modulation of the immune response by inducing autoreactive regulatory T cells could be a way of treating autoimmune disorders.
Autoimmunity 1998;27(3):159-77
Autoimmune diabetes: the role of T cells, MHC molecules and autoantigens.
Durinovic-Bello I
Diabetes Research Institute of the Academic Hospital Munchen-Schwabing, Munich, Germany. diabetes@lrz.uni-muenchen.de
Type 1 diabetes (IDDM) is a T cell mediated autoimmune disease which in part is determined genetically by its association with major histocompatibility complex (MHC) class II alleles. The major role of MHC molecules is the regulation of immune responses through the presentation of peptide epitopes of processed protein antigens to the immune system. Recently it has been demonstrated that MHC molecules associated with autoimmune diseases preferentially present peptides of other endogenous MHC proteins, that often mimic autoantigen-derived peptides. Hence, these MHC-derived peptides might represent potential targets for autoreactive T cells. It has consistently been shown that humoral autoimmunity to insulin predominantly occurs in early childhood. The cellular immune response to insulin is relatively low in the peripheral blood of patients with IDDM. Studies in NOD mice however have shown, that lymphocytes isolated from pancreatic islet infiltrates display a high reactivity to insulin and in particular to an insulin peptide B 9-23. Furthermore we have evidence that cellular autoimmunity to insulin is higher in young pre-diabetic individuals, whereas cellular reactivity to other autoantigens is equally distributed in younger and older subjects. This implicates that insulin, in human childhood IDDM and animal autoimmune diabetes, acts as an important early antigen which may target the autoimmune response to pancreatic beta cells. Moreover, we observed that in the vast majority of newly diagnosed diabetic patients or individuals at risk for IDDM, T cell reactivity to various autoantigens occurs simultaneously. In contrast, cellular reactivity to a single autoantigen is found with equal frequency in (pre)-type 1 diabetic individuals as well as in control subjects. Therefore the autoimmune response in the inductive phase of IDDM may be targeted to pancreatic islets by the cellular and humoral reactivity to one beta-cell specific autoantigen, but spreading to a set of different antigens may be a prerequisite for progression to destructive insulitis and clinical disease. Due to mimic epitopes shared by autoantigen(s), autologous MHC molecules and environmental antigens autoimmunity may spread, intramolecularly and intermolecularly and amplify upon repeated reexposure to mimic epitopes of environmental triggers.
Diabetes 1998 Oct;47(10):1594-601
HLA-DR binding analysis of peptides from islet antigens in IDDM.
Geluk A, van Meijgaarden KE, Schloot NC, Drijfhout JW, Ottenhoff TH, Roep BO
Department of Immunohematology and Blood Bank, Leiden University Medical Center, The Netherlands. geluk@rullf2.medfac.leidenuniv.nl
HLA molecules are essential for thymic education and HLA restriction of T-cell responses. We therefore analyzed the HLA-DR binding affinities of synthetic peptides covering the entire sequences of GAD65, islet cell antigen 69 (ICA69), and (pro)insulin, which are candidate antigens in the autoimmune process of T-cell-mediated destruction of the pancreatic beta-cells. Subsequently, peptide HLA-DR binding was correlated to peptide antigenicity by comparing known T-cell epitopes with their HLA-binding affinities defined in this study. The results demonstrate the following. 1) (Pro)insulin peptides display a strong binding affinity for HLA-DR2, which is associated with negative genetic predisposition to IDDM, whereas poor binding was observed for HLA-DR molecules neutrally or positively associated with IDDM. This suggests that the absence of insulin-reactive T-cells in DR2+ individuals may be explained by negative selection on high-affinity DR2 binding insulin peptides. 2) Most autoantigenic peptides display promiscuous HLA-DR binding patterns. This promiscuity in itself is not sufficient to explain the genetic association of HLA-DR with development of IDDM. 3) HLA-DR3 binding of autoantigenic GAD65 peptides is relatively weak compared with that of other known T-cell epitopes. 4) All peptide epitopes recognized by HLA-DR-restricted T-cells from either IDDM patients or GAD65-immunized HLA-DR transgenic mice bind with high affinity to their HLA-DR restriction molecule (P < 0.0006). In contrast, T-cell epitopes recognized by nondiabetic controls bind DR molecules with weak or undetectable affinity. These results thus indicate a strong correlation between antigenicity and HLA-DR binding affinity of GAD65 peptides in IDDM. Furthermore, negative thymic selection of insulin peptides in low-risk (HLA-DR2 expressing) subjects may explain the lack of autoreactivity to insulin in such individuals
J Autoimmun 1998 Apr;11(2):169-75
Cloned T cells from a recent onset IDDM patient reactive with insulin B-chain.
Schloot NC, Willemen S, Duinkerken G, de Vries RR, Roep BO
Department of Immunohematology, University Hospital Leiden, The Netherlands.
Insulin-dependent diabetes mellitus (IDDM) results from selective autoimmune destruction of insulin producing beta-cells. T-cell reactivity and autoantibodies to several islet proteins such as insulin, GAD and IA-2 are associated with IDDM in mice and men. In NOD mice, the majority of T cells from insulitis specifically recognize the insulin B-chain peptide amino acid 9-22, in contrast to the periphery where the precursor frequency is much lower. It is important to note that these cells are diabetogenic. Surprisingly, the same insulin B-chain region contains epitopes recognized by protective T cells. In fact, autoimmune diabetes in NOD mice could be prevented by prophylactic treatment with this immunodominant T-cell epitope. In humans, however, no immunodominant regions of insulin have yet been defined. We have isolated and characterized a human insulin-specific T-cell clone that was derived from peripheral blood of a newly diagnosed IDDM patient. This patient displayed weakly positive primary T-cell responses to insulin. The peptide recognized by the clone was mapped to the insulin B chain (B:11-27). Functionally, the human insulin-specific CD4+ T cells displayed a Th1/0 like cytokine profile and were restricted by HLA-DR. The previously proposed alternative superantigen-like binding of insulin-B chain peptide outside of the peptide binding groove of HLA-DR could not be confirmed, since T-cell recognition was inhibited in competition experiments of insulin-B chain peptide with HLA-DR16 binding influenza peptide HA307-319. Our results indicate that human clonal T cells isolated from a recent onset IDDM patient recognize an epitope overlapping with the insulin B-chain region that is immunodominant and potentially therapeutic in NOD mice. This observation may be useful in studying the role of insulin-specific T cells in IDDM, and may eventually help to establish peptide-based immunotherapies in IDDM.
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