Establishing long-term allograft acceptance without the requirement for continuous immunosuppression, a condition known as allograft tolerance, is a highly desirable therapeutic goal in solid organ transplantation. Determining which recipients would benefit from withdrawal or minimization of immunosuppression would be greatly facilitated by biomarkers predictive of tolerance. In this study, we identified the largest reported cohort to our knowledge of tolerant renal transplant recipients, as defined by stable graft function and receiving no immunosuppression for more than 1 year, and compared their gene expression profiles and peripheral blood lymphocyte subsets with those of subjects with stable graft function who are receiving immunosuppressive drugs as well as healthy controls. In addition to being associated with clinical and phenotypic parameters, renal allograft tolerance was strongly associated with a B cell signature using several assays. Tolerant subjects showed increased expression of multiple B cell differentiation genes, and a set of just 3 of these genes distinguished tolerant from nontolerant recipients in a unique test set of samples. This B cell signature was associated with upregulation of CD20 mRNA in urine sediment cells and elevated numbers of peripheral blood naive and transitional B cells in tolerant participants compared with those receiving immunosuppression. These results point to a critical role for B cells in regulating alloimmunity and provide a candidate set of genes for wider-scale screening of renal transplant recipients.
Anti-CD3 mAbs may prolong β cell function up to 2 years in patients with new onset Type 1 diabetes (T1DM). A randomized open label trial of anti-CD3 mAb, Teplizumab, in T1DM was stopped after 10 subjects because of increased adverse events than in a previous trial related with higher dosing of drug. Teplizumab caused transient reduction in circulating T cells, but the recovered cells were not new thymic emigrants because T cell receptor excision circles were not increased. There was a trend for reduced loss of C-peptide over 2 yrs with drug treatment (p=0.1), and insulin use was lower (p<0.001). In 4 drug treated subjects followed up to 60 months, C-peptide responses were maintained. We conclude that increased doses of Teplizumab are associated with greater adverse events without improved efficacy. The drug may marginate rather than deplete T cells. C-peptide levels may remain detectable up to 5 yrs after treatment. KeywordsType 1 diabetes mellitus; immunotherapy; anti-CD3 monoclonal antibody; T lymphocyte Corresponding author: Kevan C. Herold, MD, Yale University, 10 Amistad St, 131D, New Haven, CT 06520, Fax: 203-785-7903. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe goal of newer therapies for treatment of Type 1 diabetes (T1DM) is to arrest the autoimmune destruction of β cells for an extended period of time without the need for continuous immune suppression. FcR non-binding anti-CD3 mAbs are thought to attenuate destruction of β cells in T1DM over the first 18 months to 2 years of the disease when they are administered at diagnosis, but the duration of this effect of a treatment dose and the mechanism of action of anti-CD3 mAb are not known [1;2][3]. In two previously published randomized trials that enrolled approximately 120 subjects, a single course of treatment with two different FcR non-binding anti-CD3 mAbs was shown to improve insulin production for 18 and 24 months after diagnosis[1;2][3]. In our previous study, glycated hemoglobin levels were also improved, suggesting a benefit of drug treatment in glucose control whereas in the study of Keymeulen et al, clinical management was aimed at maintaining similar glucose control in the control and drug treated subjects to avoid any differential effect of glycemic control on β cell function [3]. Despite these differences, both studies demonstrated significantly reduced insulin usage with drug treatment.The mechanism(s) of action of FcR non-binding anti-CD3 mAbs are not clear. It is possible that the mAbs deplet...
Type 1 diabetes mellitus (T1DM) is believed to be due to the autoimmune destruction of β-cells by T lymphocytes, but a single course of rituximab, a monoclonal anti-CD20 B lymphocyte antibody can attenuate C-peptide loss over the first year of disease. The effects of B cell depletion on disease associated T cell responses have not been studied. We compare changes in lymphocyte subsets, T cell proliferative responses to disease- associated target antigens, and C-peptide levels of participants that did (responders) or did not (non-responders) show signs of β-cell preservation one year after rituximab therapy in a placebo-controlled TrialNet trial. Rituximab decreased B lymphocyte levels after 4 weekly doses of mAb. T cell proliferative responses to diabetes –associated antigens were present at baseline in 75% of anti-CD20- and 82% of placebo-treated subjects and were not different over time. However, in rituximab-treated subjects with significant C-peptide preservation at 6 months (58%), the proliferative responses to diabetes associated total (p=0.032), islet-specific (p=0.048), and neuronal auto-antigens (p=0.005) increased over the 12 month observation period. This relationship was not seen in placebo treated patients. We conclude that in patients with T1DM, anti-B cell mAb causes increased proliferative responses to diabetes antigens and attenuated β cell loss. The way in which these responses affect the disease course remains unknown.
Multiple sclerosis (MS) is an autoimmune disease characterized by infiltration of pathogenic immune cells in the central nervous system resulting in destruction of the myelin sheath and surrounding axons. We and others have previously measured the frequency of human myelin reactive T cells in peripheral blood was observed. Using T cell cloning techniques, a modest increase in the frequency of myelin reactive T cells in patients as compared to control subjects. Here, we investigated whether MOG-specific T cells could be detected and their frequency measured using DRB1*0401/MOG97–109(107E-S) tetramers in MS subjects and healthy controls expressing HLA Class II DRB1*0401. We defined the optimal culture conditions for expansion of MOG reactive T cells upon MOG peptide stimulation of PMBC. MOG97–109 reactive CD4+ T cells, isolated with DRB1*0401/MOG97–109 tetramers, after a short-term culture of PMBC with MOG97–109 peptides were detected more frequently from patients with MS as compared to healthy controls. T cell clones from single cell cloning of DRB1*0401/MOG97–109(107E-S) tetramer positive cells confirmed that these T cell clones were responsive to both the native and the substituted MOG peptide. These data indicate that autoantigen-specific T cells can be detected and enumerated from the blood of subjects utilizing Class II tetramers and the frequency of MOG97–109 reactive T cells is greater in patients with MS as compared to healthy controls.
The role of diet in type 1 diabetes development is poorly understood. Metabolites, which reflect dietary response, may help elucidate this role. We explored metabolomics and lipidomics differences between 352 cases of islet autoimmunity (IA) and controls in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. We created dietary patterns reflecting pre-IA metabolite differences between groups and examined their association with IA. Secondary outcomes included IA cases positive for multiple autoantibodies (mAb+). The association of 853 plasma metabolites with outcomes was tested at seroconversion to IA, just prior to seroconversion, and during infancy. Key compounds in enriched metabolite sets were used to create dietary patterns reflecting metabolite composition, which were then tested for association with outcomes in the nested case-control subset and the full TEDDY cohort. Unsaturated phosphatidylcholines, sphingomyelins, phosphatidylethanolamines, glucosylceramides, and phospholipid ethers in infancy were inversely associated with mAb+ risk, while dicarboxylic acids were associated with an increased risk. An infancy dietary pattern representing higher levels of unsaturated phosphatidylcholines and phospholipid ethers, and lower sphingomyelins was protective for mAb+ in the nested case-control study only. Characterization of this high-risk infant metabolomics profile may help shape the future of early diagnosis or prevention efforts.
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