Transient B-Cell Depletion with Anti-CD20 in Combination with Proinsulin DNA Vaccine or Oral Insulin: Immunologic Effects and Efficacy in NOD Mice
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{"title"=>"Transient B-Cell Depletion with Anti-CD20 in Combination with Proinsulin DNA Vaccine or Oral Insulin: Immunologic Effects and Efficacy in NOD Mice", "type"=>"journal", "authors"=>[{"first_name"=>"Ghanashyam", "last_name"=>"Sarikonda", "scopus_author_id"=>"15840872300"}, {"first_name"=>"Sowbarnika", "last_name"=>"Sachithanantham", "scopus_author_id"=>"23992838000"}, {"first_name"=>"Yulia", "last_name"=>"Manenkova", "scopus_author_id"=>"32367743000"}, {"first_name"=>"Tinalyn", "last_name"=>"Kupfer", "scopus_author_id"=>"8650767700"}, {"first_name"=>"Amanda", "last_name"=>"Posgai", "scopus_author_id"=>"55587400600"}, {"first_name"=>"Clive", "last_name"=>"Wasserfall", "scopus_author_id"=>"6603691213"}, {"first_name"=>"Philip", "last_name"=>"Bernstein", "scopus_author_id"=>"36460566200"}, {"first_name"=>"Laura", "last_name"=>"Straub", "scopus_author_id"=>"55588194600"}, {"first_name"=>"Philippe P.", "last_name"=>"Pagni", "scopus_author_id"=>"55206614000"}, {"first_name"=>"Darius", "last_name"=>"Schneider", "scopus_author_id"=>"56424009600"}, {"first_name"=>"Teresa Rodriguez", "last_name"=>"Calvo", "scopus_author_id"=>"55588025900"}, {"first_name"=>"Marilyne", "last_name"=>"Coulombe", "scopus_author_id"=>"7003595902"}, {"first_name"=>"Kevan", "last_name"=>"Herold", "scopus_author_id"=>"7006623374"}, {"first_name"=>"Ronald G.", "last_name"=>"Gill", "scopus_author_id"=>"7201801709"}, {"first_name"=>"Mark", "last_name"=>"Atkinson", "scopus_author_id"=>"35400228700"}, {"first_name"=>"Gerald", "last_name"=>"Nepom", "scopus_author_id"=>"7004387356"}, {"first_name"=>"Mario", "last_name"=>"Ehlers", "scopus_author_id"=>"7102012142"}, {"first_name"=>"Teodora", "last_name"=>"Staeva", "scopus_author_id"=>"36461782500"}, {"first_name"=>"Hideki", "last_name"=>"Garren", "scopus_author_id"=>"6603603316"}, {"first_name"=>"Lawrence", "last_name"=>"Steinman", "scopus_author_id"=>"7101723531"}, {"first_name"=>"Andrew C.", "last_name"=>"Chan", "scopus_author_id"=>"56259299100"}, {"first_name"=>"Matthias", "last_name"=>"von Herrath", "scopus_author_id"=>"7005557357"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"368327942", "issn"=>"19326203", "isbn"=>"1932-6203", "doi"=>"10.1371/journal.pone.0054712", "scopus"=>"2-s2.0-84873666112", "pmid"=>"23405091", "sgr"=>"84873666112"}, "id"=>"5d1b7afd-4235-3d88-aaa8-12afbeb71518", "abstract"=>"A recent type 1 diabetes (T1D) clinical trial of rituximab (a B cell-depleting anti-CD20 antibody) achieved some therapeutic benefit in preserving C-peptide for a period of approximately nine months in patients with recently diagnosed diabetes. Our previous data in the NOD mouse demonstrated that co-administration of antigen (insulin) with anti-CD3 antibody (a T cell-directed immunomodulator) offers better protection than either entity alone, indicating that novel combination therapies that include a T1D-related autoantigen are possible. To accelerate the identification and development of novel combination therapies that can be advanced into the clinic, we have evaluated the combination of a mouse anti-CD20 antibody with either oral insulin or a proinsulin-expressing DNA vaccine. Anti-CD20 alone, given once or on 4 consecutive days, produced transient B cell depletion but did not prevent or reverse T1D in the NOD mouse. Oral insulin alone (twice weekly for 6 weeks) was also ineffective, while proinsulin DNA (weekly for up to 12 weeks) showed a trend toward modest efficacy. Combination of anti-CD20 with oral insulin was ineffective in reversing diabetes in NOD mice whose glycemia was controlled with SC insulin pellets; these experiments were performed in three independent labs. Combination of anti-CD20 with proinsulin DNA was also ineffective in diabetes reversal, but did show modest efficacy in diabetes prevention (p = 0.04). In the prevention studies, anti-CD20 plus proinsulin resulted in modest increases in Tregs in pancreatic lymph nodes and elevated levels of proinsulin-specific CD4+ T-cells that produced IL-4. Thus, combination therapy with anti-CD20 and either oral insulin or proinsulin does not protect hyperglycemic NOD mice, but the combination with proinsulin offers limited efficacy in T1D prevention, potentially by augmentation of proinsulin-specific IL-4 production.", "link"=>"http://www.mendeley.com/research/transient-bcell-depletion-anticd20-combination-proinsulin-dna-vaccine-oral-insulin-immunologic-effec", "reader_count"=>21, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>3, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>6, "Other"=>3, "Student > Master"=>1, "Student > Bachelor"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>3, "Student > Doctoral Student"=>1, "Student > Ph. D. 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Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/482703", "https://ndownloader.figshare.com/files/482705"], "description"=>"<div><p>A recent type 1 diabetes (T1D) clinical trial of rituximab (a B cell-depleting anti-CD20 antibody) achieved some therapeutic benefit in preserving C-peptide for a period of approximately nine months in patients with recently diagnosed diabetes. Our previous data in the NOD mouse demonstrated that co-administration of antigen (insulin) with anti-CD3 antibody (a T cell-directed immunomodulator) offers better protection than either entity alone, indicating that novel combination therapies that include a T1D-related autoantigen are possible. To accelerate the identification and development of novel combination therapies that can be advanced into the clinic, we have evaluated the combination of a mouse anti-CD20 antibody with either oral insulin or a proinsulin-expressing DNA vaccine. Anti-CD20 alone, given once or on 4 consecutive days, produced transient B cell depletion but did not prevent or reverse T1D in the NOD mouse. Oral insulin alone (twice weekly for 6 weeks) was also ineffective, while proinsulin DNA (weekly for up to 12 weeks) showed a trend toward modest efficacy. Combination of anti-CD20 with oral insulin was ineffective in reversing diabetes in NOD mice whose glycemia was controlled with SC insulin pellets; these experiments were performed in three independent labs. Combination of anti-CD20 with proinsulin DNA was also ineffective in diabetes reversal, but did show modest efficacy in diabetes prevention (p = 0.04). In the prevention studies, anti-CD20 plus proinsulin resulted in modest increases in Tregs in pancreatic lymph nodes and elevated levels of proinsulin-specific CD4+ T-cells that produced IL-4. Thus, combination therapy with anti-CD20 and either oral insulin or proinsulin does not protect hyperglycemic NOD mice, but the combination with proinsulin offers limited efficacy in T1D prevention, potentially by augmentation of proinsulin-specific IL-4 production.</p> </div>", "links"=>[], "tags"=>["transient", "B-cell", "depletion", "anti-cd20", "proinsulin", "dna", "immunologic", "effects", "efficacy", "mice"], "article_id"=>155905, "categories"=>["Chemistry", "Physiology", "Immunology"], "users"=>["Ghanashyam Sarikonda", "Sowbarnika Sachithanantham", "Yulia Manenkova", "Tinalyn Kupfer", "Amanda Posgai", "Clive Wasserfall", "Philip Bernstein", "Laura Straub", "Philippe P. Pagni", "Darius Schneider", "Teresa Rodriguez Calvo", "Marilyne Coulombe", "Kevan Herold", "Ronald G. Gill", "Mark Atkinson", "Gerald Nepom", "Mario Ehlers", "Teodora Staeva", "Hideki Garren", "Lawrence Steinman", "Andrew C. Chan", "Matthias von Herrath"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0054712.s001", "https://dx.doi.org/10.1371/journal.pone.0054712.s002"], "stats"=>{"downloads"=>0, "page_views"=>44, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Transient_B_Cell_Depletion_with_Anti_CD20_in_Combination_with_Proinsulin_DNA_Vaccine_or_Oral_Insulin_Immunologic_Effects_and_Efficacy_in_NOD_Mice__/155905", "title"=>"Transient B-Cell Depletion with Anti-CD20 in Combination with Proinsulin DNA Vaccine or Oral Insulin: Immunologic Effects and Efficacy in NOD Mice", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-02-06 01:38:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/493737"], "description"=>"<p>NOD mice with hyperglycemia (2 consecutive readings of BGV>180 mg/dl), were treated with either (<b>A</b>) weekly administration of 50 µg proinsulin plasmid or (<b>B</b>) 100 (upper panel) or 250 µg of anti-CD20 alone or (<b>C</b>) 50 (upper panel) or 250 µg of anti-CD20 antibody in combination with weekly administration 50 µg of proinsulin plasmid. Each line represents one individual mouse.</p>", "links"=>[], "tags"=>["anti-cd20", "proinsulin", "plasmid", "t1d"], "article_id"=>164230, "categories"=>["Chemistry", "Physiology", "Immunology"], "users"=>["Ghanashyam Sarikonda", "Sowbarnika Sachithanantham", "Yulia Manenkova", "Tinalyn Kupfer", "Amanda Posgai", "Clive Wasserfall", "Philip Bernstein", "Laura Straub", "Philippe P. Pagni", "Darius Schneider", "Teresa Rodriguez Calvo", "Marilyne Coulombe", "Kevan Herold", "Ronald G. Gill", "Mark Atkinson", "Gerald Nepom", "Mario Ehlers", "Teodora Staeva", "Hideki Garren", "Lawrence Steinman", "Andrew C. Chan", "Matthias von Herrath"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0054712.g003", "stats"=>{"downloads"=>0, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Combination_therapy_with_anti_CD20_and_proinsulin_plasmid_does_not_offer_protection_after_T1D_onset_/164230", "title"=>"Combination therapy with anti-CD20 and proinsulin plasmid does not offer protection after T1D onset.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-06 01:10:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/493421"], "description"=>"<p>Eight week old female NOD mice were treated with 50 µg anti-CD20 and 7 days later various B-cell subsets in the spleen were analyzed. Gating strategy is shown in the top panel. Lymphocytes were gated on (<b>A</b>) B220+ (total B-cells) and further classified as FO B-cells (B220+ IgM<sup>hi</sup>, CD21<sup>int</sup>), immature B-cells (B220+ IgM<sup>hi</sup> CD21<sup>−</sup>), and MZ B-cells (B220+ IgM<sup>hi</sup> CD21<sup>hi</sup>). Total B220+ B-cell numbers were reduced in the spleen with significant reductions observed in number of follicular and immature B-cells but not MZ B-cells (<b>B</b>). Eight week old female NOD mice were given anti-CD20 i.v. Seven days post anti-CD20 treatment, frequencies of B- and T-cells in peripheral blood were determined by staining with anti-IgM/B220 for B-cells or anti-CD4/CD8 for T-cells; loss of circulating B-cells was associated with compensatory increases in CD4+ and CD8+ T-cell frequencies in NOD mice (<b>C</b>). Frequencies of circulating B-cells returned to similar levels as in untreated NOD mice by 60 days post-treatment (<b>D</b>). Data are means ± SEM. Representative data from 3 independent experiments with similar results are shown. Statistical analysis was performed using unpaired students <i>t-</i>test using Graphpad Prism software.</p>", "links"=>[], "tags"=>["murine", "anti-cd20", "preferentially", "depletes", "follicular", "marginal"], "article_id"=>163910, "categories"=>["Chemistry", "Physiology", "Immunology"], "users"=>["Ghanashyam Sarikonda", "Sowbarnika Sachithanantham", "Yulia Manenkova", "Tinalyn Kupfer", "Amanda Posgai", "Clive Wasserfall", "Philip Bernstein", "Laura Straub", "Philippe P. Pagni", "Darius Schneider", "Teresa Rodriguez Calvo", "Marilyne Coulombe", "Kevan Herold", "Ronald G. Gill", "Mark Atkinson", "Gerald Nepom", "Mario Ehlers", "Teodora Staeva", "Hideki Garren", "Lawrence Steinman", "Andrew C. Chan", "Matthias von Herrath"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0054712.g001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Novel_murine_anti_CD20_administration_preferentially_depletes_follicular_but_not_marginal_zone_B_cells_/163910", "title"=>"Novel murine anti-CD20 administration preferentially depletes follicular but not marginal zone B-cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-06 01:05:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/493871"], "description"=>"<p>Eight to ten week old prediabetic NOD mice were treated with (<b>A</b>) weekly administration of 50 µg proinsulin plasmid only or, (<b>B</b>) one-time administration of anti-CD20 alone or, (<b>C</b>) anti-CD20 administered in combination with four weekly administrations of proinsulin plasmid. Statistical tests were performed by Kaplan-Meier analysis using Graphpad Prism software.</p>", "links"=>[], "tags"=>["anti-cd20", "proinsulin", "plasmid", "prevents", "t1d"], "article_id"=>164359, "categories"=>["Chemistry", "Physiology", "Immunology"], "users"=>["Ghanashyam Sarikonda", "Sowbarnika Sachithanantham", "Yulia Manenkova", "Tinalyn Kupfer", "Amanda Posgai", "Clive Wasserfall", "Philip Bernstein", "Laura Straub", "Philippe P. Pagni", "Darius Schneider", "Teresa Rodriguez Calvo", "Marilyne Coulombe", "Kevan Herold", "Ronald G. Gill", "Mark Atkinson", "Gerald Nepom", "Mario Ehlers", "Teodora Staeva", "Hideki Garren", "Lawrence Steinman", "Andrew C. Chan", "Matthias von Herrath"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0054712.g004", "stats"=>{"downloads"=>0, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Combination_therapy_with_anti_CD20_and_proinsulin_plasmid_prevents_T1D_more_efficiently_/164359", "title"=>"Combination therapy with anti-CD20 and proinsulin plasmid prevents T1D more efficiently.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-06 01:12:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/494267"], "description"=>"<p>At 60-days post anti-CD20 mono- (MT, open bars) or combination therapy (CT, filled black bars), CD4+ T-cells were purified from treated non-diabetic NOD mice. Simultaneously, T-depleted splenocytes (TDS) were obtained from 8–10 week old NOD mice and used as APCs. 250,000 purified CD4+ T-cells were incubated with proinsulin peptide or a mutated insulin B:9–23 (B16:A) peptide in the presence of 5×10<sup>4</sup> APCs. Following 3-day incubation, IL-4 production was determined by ELISpot assay as previously described <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054712#pone.0054712-Fousteri1\" target=\"_blank\">[34]</a>. Background (media) subtracted spot numbers are shown on the Y-axis. Increased IL-4 production in response to proinsulin peptide was seen in combination therapy treated mice. Representative means ± SEM data from one of two independent experiments with similar results are shown. Statistical analysis was performed using unpaired students <i>t-</i>test using Graphpad Prism software.</p>", "links"=>[], "tags"=>["treated", "mice", "il-4", "proinsulin", "peptide"], "article_id"=>164753, "categories"=>["Chemistry", "Physiology", "Immunology"], "users"=>["Ghanashyam Sarikonda", "Sowbarnika Sachithanantham", "Yulia Manenkova", "Tinalyn Kupfer", "Amanda Posgai", "Clive Wasserfall", "Philip Bernstein", "Laura Straub", "Philippe P. Pagni", "Darius Schneider", "Teresa Rodriguez Calvo", "Marilyne Coulombe", "Kevan Herold", "Ronald G. Gill", "Mark Atkinson", "Gerald Nepom", "Mario Ehlers", "Teodora Staeva", "Hideki Garren", "Lawrence Steinman", "Andrew C. Chan", "Matthias von Herrath"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0054712.g007", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_T_cells_from_combination_therapy_treated_mice_produce_IL_4_in_response_to_proinsulin_peptide_stimulation_/164753", "title"=>"T-cells from combination therapy treated mice produce IL-4 in response to proinsulin peptide stimulation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-06 01:19:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/493972"], "description"=>"<p>Eight week old NOD mice were treated with anti-CD20 alone (monotherapy, MT) or anti-CD20 in combination with proinsulin plasmid (combination therapy, CT). At 30 days (B; left panel) or 60 days (B; right panel) post treatment (∼16 wks of age) treated non-diabetic NOD mice were sacrificed and B-cells and CD4+ T-cells were purified, from pooled splenocytes (n = 5) by positive selection using magnetic beads. Simultaneously, splenocytes were obtained from diabetic NOD mice. (<b>A</b>) Purity of B- and T-cells is shown. (<b>B</b>) 2×10<sup>6</sup> diabetic splenocytes (left panel,) or 10×10<sup>6</sup> diabetic splenocytes (right panel) were injected into 8-wk old NOD-SCID mice (4 mice per experimental group) either alone, or in combination with 3×10<sup>6</sup> B- or T-cells purified from anti-CD20 mono- or combination therapy treated mice (as indicated in figure legend). B-cells or CD4+ T-cells from either monotherapy (MT) or combination therapy (CT) mice failed to protect NOD-SCID mice from diabetes onset.</p>", "links"=>[], "tags"=>["did", "induce", "b-cells"], "article_id"=>164467, "categories"=>["Chemistry", "Physiology", "Immunology"], "users"=>["Ghanashyam Sarikonda", "Sowbarnika Sachithanantham", "Yulia Manenkova", "Tinalyn Kupfer", "Amanda Posgai", "Clive Wasserfall", "Philip Bernstein", "Laura Straub", "Philippe P. Pagni", "Darius Schneider", "Teresa Rodriguez Calvo", "Marilyne Coulombe", "Kevan Herold", "Ronald G. Gill", "Mark Atkinson", "Gerald Nepom", "Mario Ehlers", "Teodora Staeva", "Hideki Garren", "Lawrence Steinman", "Andrew C. Chan", "Matthias von Herrath"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0054712.g005", "stats"=>{"downloads"=>0, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Combination_therapy_did_not_induce_B_cells_with_regulatory_function_/164467", "title"=>"Combination therapy did not induce B-cells with regulatory function.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-06 01:14:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/493622"], "description"=>"<p>NOD mice with recent onset diabetes (2 consecutive readings of BGV>250 mg/dl), were treated with either anti-CD20 alone, oral insulin alone or a combination of both treatments, along with isotype control antibody treatment, oral diluent alone or anti-CD3 mAb treatment, as indicated in figures. These experiments were carried out in three independent labs (indicated in materials and methods) and the combined results were pooled to obtain the results shown here. The number of mice assigned to each treatment group is shown in the figure.</p>", "links"=>[], "tags"=>["B-cell", "depletion", "insulin"], "article_id"=>164121, "categories"=>["Chemistry", "Physiology", "Immunology"], "users"=>["Ghanashyam Sarikonda", "Sowbarnika Sachithanantham", "Yulia Manenkova", "Tinalyn Kupfer", "Amanda Posgai", "Clive Wasserfall", "Philip Bernstein", "Laura Straub", "Philippe P. Pagni", "Darius Schneider", "Teresa Rodriguez Calvo", "Marilyne Coulombe", "Kevan Herold", "Ronald G. Gill", "Mark Atkinson", "Gerald Nepom", "Mario Ehlers", "Teodora Staeva", "Hideki Garren", "Lawrence Steinman", "Andrew C. Chan", "Matthias von Herrath"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0054712.g002", "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Transient_B_cell_depletion_alone_or_in_combination_with_oral_insulin_does_not_reverse_diabetes_in_NOD_mice_/164121", "title"=>"Transient B-cell depletion alone or in combination with oral insulin does not reverse diabetes in NOD mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-06 01:08:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/494119"], "description"=>"<p>Eight to ten week old prediabetic NOD mice were given 50 µg of anti-CD20 either alone or in combination with weekly administration of 50 µg proinsulin plasmid for four weeks. Splenocytes and PDLN cells from mono- or combination therapy treated mice were stained with anti-IgM, -B220 (B-cells), -CD4, -CD8, -CD25 and –Foxp3. B-cell frequencies were determined by gating on IgM+ B220+ cells. Frequency of Foxp3+ cells among CD4+ T-cells was determined by gating on CD4+ cells. Cumulative frequencies of B-cells (left panel), CD4+ T-cells (middle panel), and CD4+Foxp3+ cells (right panel) in PDLN (upper panels) or spleen (lower panels) are shown at 30 days and 60 days post combination therapy. Representative data from three independent experiments with similar results is shown. Statistical analysis was performed using unpaired students <i>t-</i>test using Graphpad Prism software. Each dot represents one mouse, with mean value indicated on the graph.</p>", "links"=>[], "tags"=>["increases", "numbers", "cells", "pancreas", "draining", "lymph", "node", "60-days"], "article_id"=>164607, "categories"=>["Chemistry", "Physiology", "Immunology"], "users"=>["Ghanashyam Sarikonda", "Sowbarnika Sachithanantham", "Yulia Manenkova", "Tinalyn Kupfer", "Amanda Posgai", "Clive Wasserfall", "Philip Bernstein", "Laura Straub", "Philippe P. Pagni", "Darius Schneider", "Teresa Rodriguez Calvo", "Marilyne Coulombe", "Kevan Herold", "Ronald G. Gill", "Mark Atkinson", "Gerald Nepom", "Mario Ehlers", "Teodora Staeva", "Hideki Garren", "Lawrence Steinman", "Andrew C. Chan", "Matthias von Herrath"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0054712.g006", "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Combination_therapy_increases_numbers_of_CD4_Foxp3_cells_in_pancreas_draining_lymph_node_60_days_post_treatment_/164607", "title"=>"Combination therapy increases numbers of CD4+ Foxp3+ cells in pancreas draining lymph node 60-days post treatment.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-06 01:16:47"}

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Relative Metric

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