US20150165007A1 - Therapeutic vaccine for treatment of diabetes type 1 in children, application of the cell sorter and the method of multiplying treg cells to produce therapeutic vaccine for treatment of diabetes type 1 - Google Patents
Therapeutic vaccine for treatment of diabetes type 1 in children, application of the cell sorter and the method of multiplying treg cells to produce therapeutic vaccine for treatment of diabetes type 1 Download PDFInfo
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- US20150165007A1 US20150165007A1 US14/405,906 US201314405906A US2015165007A1 US 20150165007 A1 US20150165007 A1 US 20150165007A1 US 201314405906 A US201314405906 A US 201314405906A US 2015165007 A1 US2015165007 A1 US 2015165007A1
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Definitions
- the present invention concerns therapeutic vaccine for treatment of diabetes type 1 in children, application of the cell sorter to produce therapeutic vaccine for treatment of diabetes type 1, and the method of multiplying Treg cells in vitro to produce therapeutic vaccine for treatment of diabetes type 1.
- Diabetes type 1 is a genetically linked disease, however all researchers agree that direct damage to ⁇ cells in the pancreas is due to autoimmune reaction. Speaking in favour thereof are both the presence of antibodies towards ⁇ cell antigens, and lymphocytic infiltration to the islets of Langerhans, or the so-called insulitis, accompanied by increased ⁇ cell apoptosis.
- Treg The regulatory T-lymphocytes (Treg) form a specific population in the immune system. Although accounting for less than 1% of the leucocytes in the peripheral blood, they regulate the immune response so that swift elimination of harmful pathogens is possible while our own tissues remain protected. This is because Treg cells do not block other cells of the immune system when foreign pathogens are attacked, but prove strongly inhibiting when the immune system begins to destroy our own tissues and organs. Therefore by analogy, the immunosuppressive action of Treg cells sometimes earns them the name of the “intelligent steroids”.
- Treg cells in the organism are associated with transplant failures and incidence of allergic and autoimmune diseases.
- One of the diseases characterised by numerical deficiency of Treg cells, is diabetes type 1 where autoimmune attack destroys the patient's pancreas.
- WO 2004/110373 Known from the international publication WO 2004/110373 is a vaccine composition that comprises modified insulin B chain components suitable for use as immunogenic agents for treatment and prevention of type 1 diabetes.
- enterovirus selected from the group including: Coxsackie viruses CAV4, CAV5, CAVE, and echovirus E18, or its component.
- the description states that the listed enteroviruses are linked to diabetes type 1, which opens new therapeutic and diagnostic possibilities.
- WO 2012/001100 discloses vaccine comprising e.g. Coxsackie B virus CBV1 to prevent or treat diabetes type 1. It has been found that the virus is strongly associated with the risk of contracting diabetes type 1.
- the new therapeutic vaccine for treatment of diabetes type 1 prevents the disease effectively.
- Administration of the vaccine according to this invention to patients results in an increase in the primary marker of the pancreas function, i.e. the C-peptide level.
- the sorter employed was originally dedicated to cell therapies, which enhances its safety.
- the gist of the invention consists in the therapeutic vaccine for treatment of diabetes type 1 in children, which contains:
- the gist of this invention further consists in employing the cell sorter to produce the therapeutic vaccine for treatment of diabetes type 1, where the cells are sorted to isolate Treg cells using the algorithm sorting out the following phenotype:
- the gist of this invention also consists in the method of multiplying Treg cells in vitro to produce therapeutic vaccine for treatment of diabetes type 1, where:
- Selected for the marking are the following monoclonal antibodies: anti-CD3, anti-CD4, anti-CD8, anti-CD19, anti-CD14, anti-CD16, anti-CD25, and anti-CD127.
- the monoclonal antibodies CD3, CD4, CD8, CD19, CD14, CD16, CD25, and CD127 recognise the antigens, and are conjugated with fluorescent dyes.
- the antigen-presenting artificial cells are magnetic beads coated with anti-CD3 and anti-CD28 antibodies.
- the value at point “ ⁇ 10 days” represents the day the blood was drawn for Treg cell isolation.
- the values are given at their median, minimum, and the maximum levels.
- the statistically significant values (p ⁇ 0.05) are marked with “*”.
- the invention is illustrated with the following embodiment, which is exemplary, i.e. not limiting in nature.
- the collected blood was processed at the Regional Centre of Blood Donation and Treatment in Gdansk to extract the buffy coat and serum.
- Isolated from the buffy coat were peripheral blood mononuclear cells (PBMC) through centrifuging in the Ficoll/Uropolin concentration gradient.
- Lymphocytes T CD4+ were then separated by the immunomagnetic method (separation purity: 96-99%) using the CD4+T enrichment kit and marked with the following monoclonal antibodies (mAb): anti-CD3, anti-CD4, anti-CD8, anti-CD19, anti-CD14, anti-CD16, anti-CD25, and anti-CD127 (5 ul mAb/10 6 cells).
- Treg cells The purity of the thus isolated Treg cells was ⁇ 100% [median(min-max): 98%(97-99)].
- GMP good manufacturing practices
- the sorter is fitted with a replaceable sample flow line, which eliminates the risk of sample cross-contamination among the patients.
- applied was the CellGro medium meeting the GMP standards or X-VIVO.
- the medium was supplemented with autological inactivated serum (10%) and interleukin-2 (1000 U/ml). Introduced into the culture were the so-called antigen-presenting artificial cells [magnetic beads coated with anti-CD3 and anti-CD28 antibodies in the 1:1 proportion.
- the cells were cultivated until the appropriate number was attained, though no longer than for 2 weeks [median(min-max): 10 days (7-12)].
- the control group was made up of patients who met all above-listed criteria of inclusion in the test, except for appropriate venous access, hence were not treated with the Treg vaccine.
- the test was not randomised, nor was there a blank sample introduced, and the children of the control group were not subject to any medical intervention related to the pending tests (blood sampling, simulated transfusion, or the like). Table 1 provides the characteristics of the tested groups.
- the test was conducted in accordance with the procedure approved by the Independent Research Bioethics Committee at the Medical University of Gdansk (NKEBN/8/2010). A written consent to the above procedure was obtained from each patient and the parents.
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Abstract
The gist of the invention consists in the therapeutic vaccine for treatment of diabetes type 1 in children, which contains
-
- Treg cells CD3(+)CD4(+)CD25(high)CD127(−). Claimed too is the cell sorter used to produce the vaccine and the method of multiplying Treg cells in vitro.
Description
- The present invention concerns therapeutic vaccine for treatment of
diabetes type 1 in children, application of the cell sorter to produce therapeutic vaccine for treatment ofdiabetes type 1, and the method of multiplying Treg cells in vitro to produce therapeutic vaccine for treatment ofdiabetes type 1. - Diabetes type 1 (DM1A) is a genetically linked disease, however all researchers agree that direct damage to β cells in the pancreas is due to autoimmune reaction. Speaking in favour thereof are both the presence of antibodies towards β cell antigens, and lymphocytic infiltration to the islets of Langerhans, or the so-called insulitis, accompanied by increased β cell apoptosis.
- The regulatory T-lymphocytes (Treg) form a specific population in the immune system. Although accounting for less than 1% of the leucocytes in the peripheral blood, they regulate the immune response so that swift elimination of harmful pathogens is possible while our own tissues remain protected. This is because Treg cells do not block other cells of the immune system when foreign pathogens are attacked, but prove strongly inhibiting when the immune system begins to destroy our own tissues and organs. Therefore by analogy, the immunosuppressive action of Treg cells sometimes earns them the name of the “intelligent steroids”.
- Reduced numbers of Treg cells in the organism are associated with transplant failures and incidence of allergic and autoimmune diseases. One of the diseases characterised by numerical deficiency of Treg cells, is
diabetes type 1 where autoimmune attack destroys the patient's pancreas. - Known from the international publication WO 2004/110373 is a vaccine composition that comprises modified insulin B chain components suitable for use as immunogenic agents for treatment and prevention of
type 1 diabetes. - Known from publication WO 2012/001099, on the other hand, is vaccine containing at least one enterovirus selected from the group including: Coxsackie viruses CAV4, CAV5, CAVE, and echovirus E18, or its component. The description states that the listed enteroviruses are linked to
diabetes type 1, which opens new therapeutic and diagnostic possibilities. - Similarly, the description of WO 2012/001100 discloses vaccine comprising e.g. Coxsackie B virus CBV1 to prevent or treat
diabetes type 1. It has been found that the virus is strongly associated with the risk of contractingdiabetes type 1. - The above publications disclose vaccines intended for treatment of
diabetes type 1, nevertheless they are different than the vaccine being the gist of this invention. - In order to increase the effectiveness of treating
diabetes type 1 in children it is necessary to search for more effective and successful methods of treating the disease. - Unexpectedly, it has been found that the new therapeutic vaccine for treatment of
diabetes type 1 prevents the disease effectively. Administration of the vaccine according to this invention to patients results in an increase in the primary marker of the pancreas function, i.e. the C-peptide level. In addition, the sorter employed was originally dedicated to cell therapies, which enhances its safety. - The gist of the invention consists in the therapeutic vaccine for treatment of
diabetes type 1 in children, which contains: -
- Treg cells CD3(+)CD4(+)CD25(high)CD127(−).
- The gist of this invention further consists in employing the cell sorter to produce the therapeutic vaccine for treatment of
diabetes type 1, where the cells are sorted to isolate Treg cells using the algorithm sorting out the following phenotype: -
- CD3(+)CD4(+)CD25(high)CD127(−)doublet(−)lineage(−)dead(−).
- The gist of this invention also consists in the method of multiplying Treg cells in vitro to produce therapeutic vaccine for treatment of
diabetes type 1, where: -
- lymphocytes T CD4+ are isolated by the immunomagnetic method and marked with monoclonal antibodies,
- the sorter-isolated Treg cells are multiplied in the CellGro or X-VIVO medium supplemented with autological inactivated serum and interleukin-2,
- the culture is supplemented with artificial antigen-presenting cells in the 1:1 proportion.
- Selected for the marking are the following monoclonal antibodies: anti-CD3, anti-CD4, anti-CD8, anti-CD19, anti-CD14, anti-CD16, anti-CD25, and anti-CD127.
- The monoclonal antibodies CD3, CD4, CD8, CD19, CD14, CD16, CD25, and CD127 recognise the antigens, and are conjugated with fluorescent dyes.
- The antigen-presenting artificial cells are magnetic beads coated with anti-CD3 and anti-CD28 antibodies.
- The figures:
- FIG. 1—presents the level of Treg cells CD3+CD4+CD25highCD127-FoxP3+ in children suffering from
diabetes type 1, subject to the Treg cell therapy (n=10) over four months' observation. The value at point “−10 days” represents the day the blood was drawn for Treg cell isolation. The grey columns present the results obtained for children not administered the Treg lymphocyte infusion (control group; n=10). The values are given at their median, minimum, and the maximum levels. The statistically significant values (p<0.05) are marked with “*”. - FIG. 2—presents the C-peptide, the daily insulin dose/kg BW (DDI/kg), and the HbA1C in the tested children with
diabetes type 1, subject to the Treg cells therapy (n=10) over the four months' observation. The results for the patients not administered the cell preparation (control group; n=10) are presented in grey columns. The values are given at their median, minimum, and the maximum levels, and the statistically significant values (p<0.05) are marked with “*”. - The invention is illustrated with the following embodiment, which is exemplary, i.e. not limiting in nature.
- 250 ml of peripheral blood was sampled from each patient with the assistance from an anaesthesiologist. In the case of children whose body weight was less than 50 kg the sampled blood volume accounted for 0.5% of the body weight (BW). This concerns patients under the age of 18.
- The collected blood was processed at the Regional Centre of Blood Donation and Treatment in Gdansk to extract the buffy coat and serum. Isolated from the buffy coat were peripheral blood mononuclear cells (PBMC) through centrifuging in the Ficoll/Uropolin concentration gradient. Lymphocytes T CD4+ were then separated by the immunomagnetic method (separation purity: 96-99%) using the CD4+T enrichment kit and marked with the following monoclonal antibodies (mAb): anti-CD3, anti-CD4, anti-CD8, anti-CD19, anti-CD14, anti-CD16, anti-CD25, and anti-CD127 (5 ul mAb/106 cells). Among the listed antibodies those which recognize antigens CD14, CD16, CD19, and CD8 were conjugated with the same dye. The purpose of that dying scheme was to exclude the cells positive with respect to the listed antigens (i.e. monocytes, NK cells, lymphocytes B and cytotoxic T lymphocytes) without the need to introduce additional fluorochromes, which reduces the undesirable phenomenon of fluorescent spectra overlapping. Then, the cells were sorted to separate Tregs using a sorting cytometer to the algorithm sorting the following phenotype: CD3(+)CD4(+)CD25(high)CD127(−)doublet(−)lineage(−)dead(−).
- The adopted exemplary dying scheme (antibody; dye name acronym, full name of the dye)
-
- antiCD127 FITC (Fluorescein isothiocyanate)
- antiCD25 PE (phycoerythrin)
- antiCD16 PerCP (Peridinin Chlorophyll Protein Complex)
- antiCD19 PerCP (Peridinin Chlorophyll Protein Complex)
- antiCD8 PerCP (Peridinin Chlorophyll Protein Complex)
- antiCD14 PerCP (Peridinin Chlorophyll Protein Complex)
- antiCD4 APC (allophycocyanin)
- antiCD3 Pacific Blue/Pacific Blue
or equivalents evoked to emit fluorescent light in similar spectrum ranges.
- The purity of the thus isolated Treg cells was ˜100% [median(min-max): 98%(97-99)]. An important modification compared to our earlier procedure consisted in applying the Influx cell sorter designed in accordance with the good manufacturing practices (GMP). The sorter is fitted with a replaceable sample flow line, which eliminates the risk of sample cross-contamination among the patients. Moreover, applied was the CellGro medium meeting the GMP standards or X-VIVO. The medium was supplemented with autological inactivated serum (10%) and interleukin-2 (1000 U/ml). Introduced into the culture were the so-called antigen-presenting artificial cells [magnetic beads coated with anti-CD3 and anti-CD28 antibodies in the 1:1 proportion. The cells were cultivated until the appropriate number was attained, though no longer than for 2 weeks [median(min-max): 10 days (7-12)].
- The above indicated modifications allowed the attainment of substantially improved stability and quality of the cultured Treg cells in the final product. The actual application of the preparation in therapy was conditional on satisfaction of the following criteria: factor FoxP3 expression above 90% [median(min-max)=93%(90-97)], positive result of the IFNγ production inhibition test, and negative results of microbiological tests—no genetic material of the HBV, HCV, or HIV viruses, and no bacterial contamination in the culture supernatants. Before infusion, the cells were washed with PBS, the magnetic beads removed, and administered in slow intravenous injection in 250 ml 0.9% NaCl under supervision of the anaesthesiologist within 1 h after the product release. The therapeutic dose was 20×106/kg BW (n=6), or 10×106/kg BW (n=4; whenever no higher number of cells had been achieved upon cultivation for 2 weeks), or 30×106/kg body weight. The control group was made up of patients who met all above-listed criteria of inclusion in the test, except for appropriate venous access, hence were not treated with the Treg vaccine. The test was not randomised, nor was there a blank sample introduced, and the children of the control group were not subject to any medical intervention related to the pending tests (blood sampling, simulated transfusion, or the like). Table 1 provides the characteristics of the tested groups. The test endpoints were as follows: the fasting C-peptide level, the HbA1c concentration, the insulin requirement, especially the daily dose (DDI)=0.5 UI/kg BW adopted as the remission indicator. The test was conducted in accordance with the procedure approved by the Independent Research Bioethics Committee at the Medical University of Gdansk (NKEBN/8/2010). A written consent to the above procedure was obtained from each patient and the parents.
- None of the patients was observed to develop any serious infections, episodes of acute hyper-/hypoglycaemia, or any other undesirable side effects of the Tregs vaccine at any time over the test period. In case of one patient the Treg cell infusion date coincided with flu diagnosed a day after the Treg cells had been administered.
- Beginning on the infusion date and continuously afterwards the recorded Treg lymphocyte per cent level in the peripheral blood was significantly increased (Wilcoxon test, p=0.04) (
FIG. 1 ). - Two weeks after the Treg cell infusion all patients subject to the therapy were observed to demonstrate substantially reduced demand for exogenous insulin and a reduced HbA1c level (
FIG. 2 ). - The first significant differences between the test group and the patients of the control group were observed six months after formulation of the diabetes diagnosis (5-6 months after the Treg cell infusion). The treated patients continued in the remission phase [DDI median(min-max)=0.24 UI/kg BW (0-0.55)], whereas the control group experienced the end of remission [DDI median(min-max)=0.55 UI/kg BW (0.43-0.69)] (Mann-Whitney U test, p=0.03). In addition, the children treated with Treg cells proved to have a significantly higher level of C-peptide [median(min-max): 0.65 ng/ml (0.46-2.11) vs. 0.40 ng/ml (0.15-0.54)] (Mann-Whitney U test, p=0.04) (
FIG. 3 ). No differences with respect to therapy effectiveness were observed in the patients who had been administered Treg cells dosed at 20×106/kg BW or 10×106/kg BW. Therefore, all results of the test group are presented en block. -
- 1. Marek N, Krzystyniak A, Ergenc I, Cochet O, Misawa R, Wang L J, Goçb K, Wang X, Kilimnik G, Hara M, Kizilel S, Trzonkowski P, Millis J M, Witkowski P. Coating human pancreatic islets with CD4(+)CD25(high)CD127(−) regulatory T cells as a novel approach for the local immunoprotection. Ann Surg. 2011; 254(3):512-8; discussion 518-9.
- 2. Marek N, Bieniaszewska M, Krzystyniak A, Juscinska J, Mysliwska J, Witkowski P, Hellmann A, Trzonkowski P. The time is crucial for exvivo expansion of T regulatory cells for therapy. Cell Transplant. 2011 (20):1747-1758;
- 3. Trzonkowski P. All roads lead to T regulatory cells. Transplantation. 2011; 91(2):150-1.
- 4. Trzonkowski P, Bieniaszewska M, Juścińska J, Dobyszuk A, Krzystyniak A, Marek N, Myśliwska J, Hellmann A. First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127− T regulatory cells. Clin Immunol. 2009; 133(1):22-6.
- 5. Trzonkowski P, Szaryńska M, Myśliwska J, My{grave over (s)}liwski A. Ex vivo expansion of CD4(+)CD25(+) T regulatory cells for immunosuppressive therapy. Cytometry A. 2009; 75(3):175-88.
- 6. Ryba M, Marek N, Hak , Rybarczyk-Kapturska K, Myśliwiec M, Trzonkowski P, Myśliwska J. Anti-TNF rescue CD4+Foxp3+ regulatory T cells in patients with
type 1 diabetes from effects mediated by TNF. Cytokine. 2011; 55(3):353-61. - 7. Trzonkowski P, Szmit E, Myśliwska J, Myśliwski A. CD4+CD25+ T regulatory cells inhibit cytotoxic activity of CTL and NK cells in humans-impact of immunosenescence. Clin Immunol. 2006; 119(3):307-16.
- 8. Trzonkowski P, Szmit E, My{grave over (s)}liwska J, Dobyszuk A, Myśliwski A. CD4+CD25+ T regulatory cells inhibit cytotoxic activity of T CD8+ and NK lymphocytes in the direct cell-to-cell interaction. Clin Immunol. 2004; 112(3):258-67.
- 9. Trzonkowski P, Zaucha J M, Mysliwska J, Balon J, Szmit E, Halaburda K, Bieniaszewska M, Mlotkowska M, Hellmann A, Mysliwski A. Differences in kinetics of donor lymphoid cells in response to G-CSF administration may affect the incidence and severity of acute GvHD in respective HLA-identical sibling recipients. Med Oncol. 2004; 21(1):81-94.
- 10. Goçb K, Krzystyniak A, Marek-Trzonkowska N, Misawa R, Wang L J, Wang X, Cochet O, Tibudan M, Langa P, Millis J M, Trzonkowski P., Witkowski P. Impact of culture medium on CD4+ CD25highCD127lo/neg Treg expansion for the purpose of clinical application. Int Immunopharmacol. 2013. doi:pii: S1567-5769(13)00058-1. 10.1016/j.intimp.2013.02.016
Claims (6)
1. Therapeutic vaccine for treatment of diabetes type 1 in children characterised in that it contains:
Treg cells CD3(+)CD4(+)CD25(high)CD127(−)
2. Application of the cell sorter to produce the vaccine defined in claim 1 , characterised in that the cells are sorted to isolate Treg cells using the algorithm sorting the following phenotype:
CD3(+)CD4(+)CD25(high)CD127(−)doublet(−)lineage(−)dead(−).
3. The method of multiplying Treg cells in vitro to produce the vaccine defined in claim 1 , characterised in that:
lymphocytes T CD4+ are isolated by the immunomagnetic method and marked with monoclonal antibodies,
the sorter-isolated Treg cells are multiplied in the CellGro CellGro or X-VIVO medium supplemented with autological inactivate serum and interleukin-2,
the culture is added artificial antigen-presenting cells in the 1:1 proportion.
4. The method according to claim 3 , characterised in that selected for the marking are the following monoclonal antibodies: anti-CD3, anti-CD4, anti-CD8, anti-CD19, anti-CD14, anti-CD16, anti-CD25, and anti-CD127.
5. The method according to claim 3 , characterised in that the monoclonal antibodies CD3, CD4, CD8, CD19, CD14, CD16, CD25, and CD127 recognise the antigens, and are conjugated with fluorescent dyes.
6. The method according to claim 3 , characterised in that the antigen-presenting artificial cells are magnetic beads coated with anti-CD3 and anti-CD28 antibodies.
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PL399447A PL218400B1 (en) | 2012-06-06 | 2012-06-06 | A vaccine for the treatment of type 1 diabetes in children, the use of a cell sorter and a method for proliferation of Treg cells producing a vaccine for the treatment of type 1 diabetes |
PLP.399447 | 2012-06-06 | ||
PCT/PL2013/000072 WO2013184011A1 (en) | 2012-06-06 | 2013-06-04 | Therapeutic vaccine for treatment of diabetes type 1 in children, application of the cell sorter and the method of multiplying treg cells to produce therapeutic vaccine for treatment of diabetes type 1 |
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US15/852,227 Active US11944672B2 (en) | 2012-06-06 | 2017-12-22 | Therapeutic vaccine for treatment of diabetes type 1 in children, application of the cell sorter and the method of multiplying Treg cells to produce therapeutic vaccine for treatment of diabetes type 1 |
US16/661,038 Abandoned US20200054724A1 (en) | 2012-06-06 | 2019-10-23 | Therapeutic vaccine for treatment of diabetes type 1 in children, application of the cell sorter and the method of multiplying treg cells to produce therapeutic vaccine for treatment of diabetes type 1 |
US18/588,535 Pending US20240197848A1 (en) | 2012-06-06 | 2024-02-27 | Therapeutic vaccine for treatment of diabetes type 1 in children, application of the cell sorter and the method of multiplying treg cells to produce therapeutic vaccine for treatment of diabetes type 1 |
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US16/661,038 Abandoned US20200054724A1 (en) | 2012-06-06 | 2019-10-23 | Therapeutic vaccine for treatment of diabetes type 1 in children, application of the cell sorter and the method of multiplying treg cells to produce therapeutic vaccine for treatment of diabetes type 1 |
US18/588,535 Pending US20240197848A1 (en) | 2012-06-06 | 2024-02-27 | Therapeutic vaccine for treatment of diabetes type 1 in children, application of the cell sorter and the method of multiplying treg cells to produce therapeutic vaccine for treatment of diabetes type 1 |
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US10709774B2 (en) | 2013-04-26 | 2020-07-14 | Enzo Biochem, Inc. | Immunomodulatory pharmaceutical compositions |
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PL236046B1 (en) | 2015-12-17 | 2020-11-30 | Gdanski Univ Medyczny | Method of in-vitro multiplication of regulatory T cells (Treg) |
EP3985106A1 (en) | 2020-10-16 | 2022-04-20 | Uniwersytet Gdanski | Conditioned regulatory t cell population with enhanced therapeutic potential, method for obtaining of regulatory t cell population and the medical use of regulatory t cell population |
EP3985105A1 (en) | 2020-10-16 | 2022-04-20 | Uniwersytet Gdanski | Conditioned regulatory t cell population tregs with enhanced therapeutic potential, method for obtaining of conditioned tregs and the medical use of the tregs population |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090142308A1 (en) * | 2006-04-25 | 2009-06-04 | Joslin Diabetes Center, Inc. | Methods for treating autoimmune disease by inducing autoantigen-specific regulatory CD4+ T cells |
US20090208471A1 (en) * | 2006-04-07 | 2009-08-20 | Yun Theodore J | Isolation and Use of Human Regulatory T Cells |
US20090232774A1 (en) * | 2005-08-24 | 2009-09-17 | Yeda Research And Development Co. Ltd. | Universal donor-derived tolerogenic cells for inducing non-syngeneic transplantation tolerance |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CA2527830A1 (en) | 2003-06-02 | 2004-12-23 | Mercia Pharma, Inc. | Therapeutic vaccine compositions for the treatment of type 1 diabetes |
JP2006280307A (en) * | 2005-04-01 | 2006-10-19 | Kyoto Univ | Method for producing controllable t cell |
EP2402028A1 (en) | 2010-07-01 | 2012-01-04 | Sanofi Pasteur | Enterovirus vaccines for preventing and treating type 1 diabetes (II) |
EP2402029A1 (en) | 2010-07-01 | 2012-01-04 | Sanofi Pasteur | Enterovirus vaccines for preventing or treating type 1 diabetes (III) |
US9481866B2 (en) * | 2011-12-16 | 2016-11-01 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Methods of producing T cell populations enriched for stable regulatory T-cells |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090232774A1 (en) * | 2005-08-24 | 2009-09-17 | Yeda Research And Development Co. Ltd. | Universal donor-derived tolerogenic cells for inducing non-syngeneic transplantation tolerance |
US20090208471A1 (en) * | 2006-04-07 | 2009-08-20 | Yun Theodore J | Isolation and Use of Human Regulatory T Cells |
US20090142308A1 (en) * | 2006-04-25 | 2009-06-04 | Joslin Diabetes Center, Inc. | Methods for treating autoimmune disease by inducing autoantigen-specific regulatory CD4+ T cells |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10709774B2 (en) | 2013-04-26 | 2020-07-14 | Enzo Biochem, Inc. | Immunomodulatory pharmaceutical compositions |
US11173195B2 (en) | 2013-04-26 | 2021-11-16 | Enzo Biochem, Inc. | Immunomodulatory pharmaceutical compositions including a synthetic peptide and transforming growth factor beta |
CN114008192A (en) * | 2019-04-30 | 2022-02-01 | 加利福尼亚大学董事会 | Bead-free ex vivo expansion of human regulatory T cells |
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