Klinman, Dennis M. (Potomac, MD, US)
Gursel, Mayda (Ankara, TR)
Verthelyi, Daniela (Potomac, MD, US)

Plaque It!

10/486755

04/08/2008

08/13/2002

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The United States of America as represented by Secretary of the Department of Health and Human Services (Washington, DC, US)

514/44

536/24.100, 536/23.100

A61K31/70

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4758553	Compositions of nucletic acid components for nutritional replenishment	July, 1988	Ogoshi
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4994442	Method for stimulation or repair and regeneration of intestinal gut cells in infants and enhancing the immune response of t-cells	February, 1991	Gil et al.
5023243	Oligonucleotide therapeutic agent and method of making same	June, 1991	Tullis
5066500	Infant formulas and nutrition products enriched with nucleosides and/or nucleotides and processes for their preparation	November, 1991	Gil et al.
5231085	Compositions and methods for the enhancement of host defense mechanisms	July, 1993	Alexander et al.
5234811	Assay for a new gaucher disease mutation	August, 1993	Beutler et al.
5248670	Antisense oligonucleotides for inhibiting herpesviruses	September, 1993	Draper et al.
5268365	Nucleotides, nucleosides, and nucleobases in immune function restoration enhancement or maintenance	December, 1993	Rudolph et al.
5288509	Method for the preparation of a yeast extract, said yeast extract, its use as a food flavour, and a food composiiton comprising the yeast extract	February, 1994	Potman et al.
5488039	Method for the production of an enteral formula containing ribo-nucleotides	January, 1996	Masor et al.
5492899	Infant nutritional formula with ribo-nucleotides	February, 1996	Masor et al.
5585479	Antisense oligonucleotides directed against human ELAM-I RNA	December, 1996	Hoke et al.
5591721	Method of down-regulating gene expression	January, 1997	Agrawal et al.
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5614191	IL-13 receptor specific chimeric proteins and uses thereof	March, 1997	Puri et al.
5650156	Methods for in vivo delivery of nutriceuticals and compositions useful therefor	July, 1997	Grinstaff et al.
5663153	Immune stimulation by phosphorothioate oligonucleotide analogs	September, 1997	Hutcherson et al.
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5684147	Therapeutic anti-HIV anti-viral oligonucleotides and pharmaceutical formulations thereof	November, 1997	Agrawal et al.
5700590	Nutritional formula with ribo-nucleotides	December, 1997	Masor et al.
5712256	Ribonucleotide preparations and uses thereof	January, 1998	Kulkarni et al.
5723335	Immune stimulation by phosphorothioate oligonucleotide analogs	March, 1998	Hutcherson et al.
5786189	Vaccine	July, 1998	Locht et al.
5804566	Methods and devices for immunizing a host through administration of naked polynucleotides with encode allergenic peptides	September, 1998	Carson et al.
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5976580	Nutrient formulation and process for enhancing the health, livability, cumulative weight gain or feed efficiency in poultry and other animals	November, 1999	Ivey et al.
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6194388	Immunomodulatory oligonucleotides	February, 2001	Krieg et al.
6207646	Immunostimulatory nucleic acid molecules	March, 2001	Krieg et al.
6214806	Use of nucleic acids containing unmethylated CPC dinucleotide in the treatment of LPS-associated disorders	April, 2001	Krieg et al.
6218371	Methods and products for stimulating the immune system using immunotherapeutic oligonucleotides and cytokines	April, 2001	Krieg et al.
6239116	Immunostimulatory nucleic acid molecules	May, 2001	Krieg et al.
6339068	Vectors and methods for immunization or therapeutic protocols	January, 2002	Krieg et al.
6406705	Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant	June, 2002	Davis et al.
6423539	Adjuvant treatment by in vivo activation of dendritic cells	July, 2002	Fong et al.
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6429199	Immunostimulatory nucleic acid molecules for activating dendritic cells	August, 2002	Krieg et al.
6498148	Immunization-free methods for treating antigen-stimulated inflammation in a mammalian host and shifting the host's antigen immune responsiveness to a Th1 phenotype	December, 2002	Raz
6514948	Method for enhancing an immune response	February, 2003	Raz et al.
6534062	Methods for increasing a cytotoxic T lymphocyte response in vivo	March, 2003	Raz et al.
6552006	Immunomodulatory polynucleotides in treatment of an infection by an intracellular pathogen	April, 2003	Raz et al.
6562798	Immunostimulatory oligonucleotides with modified bases and methods of use thereof	May, 2003	Schwartz
6589940	Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof	July, 2003	Raz et al.
6610661	Immunostimulatory polynucleotide/immunomodulatory molecule conjugates	August, 2003	Carson et al.
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20010044416	Immunostimulatory nucleic acids for inducing a Th2 immune response	November, 2001	McCluskie et al.
20010046967	Methods of preventing and treating respiratory viral infection using immunomodulatory polynucleotide	November, 2001	Van Nest
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20020055477	Immunomodulatory formulations and methods for use thereof	May, 2002	Van Nest et al.
20020064515	Methods and products for stimulating the immune system using immunotherapeutic oligonucleotides and cytokines	May, 2002	Krieg et al.
20020065236	CpG reduced plasmids and viral vectors	May, 2002	Yew et al.
20020086295	Immunomodulatory polynucleotides in treatment of an infection by an intracellular pathogen	July, 2002	Raz et al.
20020086839	Inhibitors of DNA immunostimulatory sequence activity	July, 2002	Raz et al.
20020090724	Activation of regulatory T cells by alpha-melanocyte stimulating hormone	July, 2002	Taylor et al.
20020091095	Modulation of Fas and FasL expression	July, 2002	Phillips et al.
20020091097	Nucleic acids for the prevention and treatment of sexually transmitted diseases	July, 2002	Bratzler et al.
20020098199	Methods of suppressing hepatitis virus infection using immunomodulatory polynucleotide sequences	July, 2002	Van Nest et al.
20020098205	Composition of multipurpose high functional alkaline solution composition, preparation thereof, and for the use of nonspecific immunostimulator	July, 2002	Choi et al.
20020098980	Composition of multipurpose high functional alkaline solution composition, preparation thereof, and for the use of nonspecific immunostimulator	July, 2002	Choi et al.
20020107212	Methods of reducing papillomavirus infection using immunomodulatory polynucleotide sequences	August, 2002	Van Nest et al.
20020110569	Vaccines for broad spectrum protection against diseases caused by neisseria meningitidis	August, 2002	Granoff et al.
20020111323	Introduction of naked DNA or RNA encoding non-human vertebrate peptide hormones or cytokines into a non-human vertebrate	August, 2002	Martin et al.
20020136776	Microparticle compositions and methods for the manufacture thereof	September, 2002	Fang et al.
20020137714	Modulation of immunostimulatory activity of immunostimulatory oligonucleotide analogs by positional chemical changes	September, 2002	Kandimalla et al.
20020142974	IMMUNE ACTIVATION BY DOUBLE-STRANDED POLYNUCLEOTIDES	October, 2002	Kohn et al.
20020142977	Methods for increasing a cytotoxic T lymphocyte response in vivo	October, 2002	Raz et al.
20020142978	Synergistic improvements to polynucleotide vaccines	October, 2002	Raz et al.
20020156033	Immunostimulatory nucleic acids and cancer medicament combination therapy for the treatment of cancer	October, 2002	Bratzler et al.
20020164341	Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant	November, 2002	Davis et al.
20020165178	Immunostimulatory nucleic acids for the treatment of anemia, thrombocytopenia, and neutropenia	November, 2002	Schetter et al.
20020183272	Methods and compositions for vaccination comprising nucleic acid and/or polypeptide sequences of chlamydia	December, 2002	Johnston et al.
20020197269	Pharmaceutical composition for immunomodulation and preparation of vaccines	December, 2002	Lingnau et al.
20020198165	Nucleic acids for the prevention and treatment of gastric ulcers	December, 2002	Bratzler et al.
20030003579	Dendritic cells; methods	January, 2003	Kadowakie t al.
20030022849	Nucleic acid vaccines for prevention of flavivirus infection	January, 2003	Chang
20030022852	Biodegradable immunomodulatory formulations and methods for use thereof	January, 2003	Van Nest et al.
20030026782	IMMUNOMODULATORY OLIGONUCLEOTIDES	February, 2003	Krieg
20030026801	Methods for enhancing antibody-induced cell lysis and treating cancer	February, 2003	Weiner et al.
20030049266	Immunomodulatory polynucleotides and methods of using the same	March, 2003	Fearon et al.
20030050261	Immunostimulatory nucleic acid molecules	March, 2003	Krieg et al.
20030050263	Methods and products for treating HIV infection	March, 2003	Krieg et al.
20030050268	Immunostimulatory nucleic acid for treatment of non-allergic inflammatory diseases	March, 2003	Krieg et al.
20030052839	Stabilized viral envelope proteins and uses thereof	March, 2003	Binley et al.
20030055014	Inhibition of angiogenesis by nucleic acids	March, 2003	Bratzler
20030059773	Immunomodulatory formulations and methods for use thereof	March, 2003	Van Nest et al.
20030060440	Oligodeoxynucleotide and its use to induce an immune response	March, 2003	Klinman et al.
20030064064	Methods of treating IgE-associated disorders and compositions for use therein	April, 2003	Dina
20030072762	Compositions comprising immunostimulatory oligonucleotides and uses thereof to enhance Fc receptor-mediated immunotherapies	April, 2003	Van de Winkel et al.
20030073142	Immunoglobulin E vaccines and methods of use thereof	April, 2003	Chen et al.
20030078223	Compositions and methods for modulating an immune response	April, 2003	Raz et al.
20030091599	Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant	May, 2003	Davis et al.
20030092663	Immunization-free methods for treating antigen-stimulated inflammation in a mammalian host and shifting the host's antigen immune responsiveness to a Th1 phenotype	May, 2003	Raz
20030096417	Vaccination against feline immunodeficiency virus	May, 2003	Fischer
20030100527	Immunostimulatory nucleic acid molecules for activating dendritic cells	May, 2003	Krieg et al.
20030104044	Compositions for stimulating cytokine secretion and inducing an immune response	June, 2003	Semple et al.
20030104523	Process for high throughput screening of CpG-based immuno-agonist/antagonist	June, 2003	Lipford et al.
20030109469	Recombinant gene expression vectors and methods for use of same to enhance the immune response of a host to an antigen	June, 2003	Carson et al.
20030119773	Method for enhancing an immune response	June, 2003	Raz et al.
20030119774	Compositions and methods for stimulating an immune response	June, 2003	Foldvari et al.
20030119776	Modulation of Fas and FasL expression	June, 2003	Phillips et al.
20030125284	Agents that modulate DNA-PK activity and methods of use thereof	July, 2003	Raz et al.
20030129251	Biodegradable immunomodulatory formulations and methods for use thereof	July, 2003	Van Nest et al.
20030130217	Method for treating inflammatory bowel disease and other forms of gastrointestinal inflammation	July, 2003	Raz et al.
20030133988	Immunomodulatory compositions, formulations, and methods for use thereof	July, 2003	Fearon et al.
20030135875	Models of chronic and acute inflammatory diseases	July, 2003	Ehrhardt et al.
20030138413	Methods for treating cancer	July, 2003	Vicari et al.
20030138453	Microparticles for delivery of heterologous nucleic acids	July, 2003	O'Hagan et al.
20030139364	Methods and products for enhancing immune responses using imidazoquinoline compounds	July, 2003	Krieg et al.
20030143213	Methods for increasing a cytotoxic T lymphocyte response in vivo	July, 2003	Raz et al.
20030143743	Transfection of eukaryontic cells with linear polynucleotides by electroporation	July, 2003	Schuler et al.
20030144229	Multiple CpG oligodeoxynucleotides and their use to induce an immune response	July, 2003	Klinman et al.
20030157717	Linear DNA fragments for gene expression	July, 2003	Draghia-Akli
20030147870	Methods for increasing a cytotoxic T lymphocyte response in vivo	August, 2003	Raz et al.
20030148316	Methods and compositions relating to plasmacytoid dendritic cells	August, 2003	Lipford et al.
20030148976	Combination motif immune stimulatory oligonucleotides with improved activity	August, 2003	Krieg et al.
20030148983	Polynucleotide therapy	August, 2003	Fontoura et al.
20030158136	Materials and methods relating to immune responses to fusion proteins	August, 2003	Rice et al.
20030165478	Stabilized synthetic immunogen delivery system	September, 2003	Sokoll
20030166001	Toll-like receptor 3 signaling agonists and antagonists	September, 2003	Lipford
20030170273	Adjuvant compositions	September, 2003	O'Hagan et al.
20030171321	Immunostimulatory oligodeoxynucleotides	September, 2003	Schmidt et al.
20030175731	Chimeric immunomodulatory compounds and methods of using the same - I	September, 2003	Fearon et al.
20030176373	Agents that modulate DNA-PK activity and methods of use thereof	September, 2003	Raz et al.
20030176389	Method for treating inflammatory bowel disease and other forms of gastrointestinal inflammation	September, 2003	Raz et al.
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20030181406	CpG-like nucleic acids and methods of use thereof	September, 2003	Schetter et al.
20030185848	Methods and compositions for vaccination comprising nucleic acid and/or polypeptide sequences of Chlamydia psittaci	October, 2003	Johnston et al.
20030185900	Composition of multipurpose high functional alkaline solution composition, preparation thereof, and for the use of nonspecific immunostimulator	October, 2003	Choi et al.
20030186921	Recombinant gene expression vectors and methods for use of same to enhance the immune response of a host to an antigen	October, 2003	Carson et al.
20030191079	Methods for treating and preventing infectious disease	October, 2003	Krieg et al.
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20030203861	Recombinant gene expression vectors and methods for use of same to enhance the immune response of a host to an antigen	October, 2003	Carson et al.
20030206967	Composition of multipurpose high functional alkaline solution composition, preparation thereof, and for the use of nonspecific immunostimulator	November, 2003	Choi et al.
20030207287	Non-stochastic generation of genetic vaccines	November, 2003	Short
20030212026	Immunostimulatory nucleic acids	November, 2003	Krieg et al.
20030212028	Immunomodulatory polynucleotides in treatment of an infection by an intracellular pathogen	November, 2003	Raz et al.
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20030220277	Methylation of plasmid vectors	November, 2003	Yew et al.
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20030225016	Chimeric immunomodulatory compounds and methods of using the same - III	December, 2003	Fearon et al.
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20040009942	Methods of preventing and treating respiratory viral infection using immunomodulatory polynucleotide sequences	January, 2004	Van Nest
20040009949	Method for treating autoimmune or inflammatory diseases with combinations of inhibitory oligonucleotides and small molecule antagonists of immunostimulatory CpG nucleic acids	January, 2004	Krieg
20040013686	Molecular mimetics of meningococcal B epitopes which elicit functionally active antibodies	January, 2004	Granoff et al.
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WO/2000/014217	March, 2000			G-MOTIF OLIGONUCLEOTIDES AND USES THEREOF
WO/2000/020039	April, 2000			METHODS AND ADJUVANTS FOR STIMULATING MUCOSAL IMMUNITY
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WO/2000/061151	October, 2000			OLIGODEOXYNUCLEOTIDE AND ITS USE TO INDUCE AN IMMUNE RESPONSE
WO/2000/062787	October, 2000			METHODS AND COMPOSITIONS FOR USE IN POTENTIATING ANTIGEN PRESENTATION BY ANTIGEN PRESENTING CELLS
WO/2000/067023	November, 2000			SCREENING FOR IMMUNOSTIMULATORY DNA FUNCTIONAL MODIFYERS
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WO/2001/000232	January, 2001			USE OF CPG AS AN ADJUVANT FOR HIV VACCINE
WO/2001/002007	January, 2001			METHOD FOR ENHANCING AN IMMUNE RESPONSE
WO/2001/012223	February, 2001			METHODS OF MODULATING AN IMMUNE RESPONSE USING IMMUNOSTIMULATORY SEQUENCES AND COMPOSITIONS FOR USE THEREIN
WO/2001/012804	February, 2001			MODULATION OF OLIGONUCLEOTIDE CpG-MEDIATED IMMUNE STIMULATION BY POSITIONAL MODIFICATION OF NUCLEOSIDES
WO/2001/022990	April, 2001			METHODS RELATED TO IMMUNOSTIMULATORY NUCLEIC ACID-INDUCED INTERFERON
WO/2001/051500	July, 2001			OLIGODEOXYNUCLEOTIDE AND ITS USE TO INDUCE AN IMMUNE RESPONSE
WO/2001/055341	August, 2001			IMMUNOMODULATORY POLYNUCLEOTIDES IN TREATMENT OF AN INFECTION BY AN INTRACELLULAR PATHOGEN
WO/2001/068077	September, 2001			IMMUNOSTIMULATORY POLYNUCLEOTIDE SEQUENCES FOR USE IN PREVENTING AND TREATING VIRAL INFECTIONS
WO/2001/068103	September, 2001			TREATMENT OF HERPES INFECTION USING IMMUNOMODULATORY POLYNUCLEOTIDE SEQUENCES
WO/2001/068116	September, 2001			IMMUNOSTIMULATORY POLYNUCLEOTIDE SEQUENCES FOR USE IN PREVENTING AND TREATING RESPIRATORY VIRAL INFECTIONS
WO/2001/068117	September, 2001			IMMUNOSTIMULATORY POLYNUCLEOTIDE SEQUENCES FOR USE IN PREVENTING AND TREATING VIRAL INFECTIONS
WO/2002/069369	September, 2002			CPG-LIKE NUCLEIC ACIDS AND METHODS OF USE THEREOF

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Li, Janice Q.

Klarquist Sparkman, LLP

PRIORITY CLAIM

This is the § 371 U.S. National Stage of International Application No. PCT/US02/25732, filed Aug. 13, 2002, which was published in English under PCT Article 21(2), which in turn claims the benefit of U.S. Provisional Application No. 60/312,190, filed Aug. 14, 2001, which is incorporated by reference herein in its entirety.

The invention claimed is:

1. A method for generating a mature dendritic cell, comprising contacting a dendritic cell precursor with an effective amount of an oligodeoxynucleotide of at least about 16 nucleotides in length comprising a sequence represented by the following formula:
5′X₁X₂X₃Pu₁Py₂CpGPu₃Py₄X₄X₅X₆(W)_M(G)_N−3′ wherein the central CpG motif is unmethylated, Pu is a purine nucleotide, Py is a pyrimidine nucleotide, X and W are any nucleotide, M is any integer from 0 to 10, and N is any integer from 4 to 10, wherein X₁X₂X₃ Pu₁Py₂ and Pu₃Py₄X₄X₅X₆ are self complementary, thereby generating a mature dendritic cell.

2. A method for generating a mature dendritic cell, comprising contacting a dendritic cell precursor with an effective amount of an oligodeoxynucleotide of at least about 16 nucleotides in length comprising a sequence represented by the following formula:
5′X₁X₂X₃Pu₁Py₂CpGPu₃Py₄X₄X₅X₆(W)_M(G)_N−3′ wherein the central CpG motif is unmethylated, Pu is a purine nucleotide, Py is a pyrimidine nucleotide, X and W are any nucleotide, M is any integer from 0 to 10, and N is any integer from 4 to 10, wherein X₁X₂X_{3 AND} X₄X₅X₆ are self complementary, thereby generating a mature dendritic cell.

3. A method for generating a mature dendritic cell, comprising contacting a dendritic cell precursor with an effective amount of an oligodeoxynucleotide of at least about 16 nucleotides in length comprising the sequence GGTGCATCGATGCAGGGGGG (SEQ ID NO: 1); or GGTGCACCGGTGCAGGGGGG (SEQ ID NO:2).

4. The method of claim 1, further comprising contacting the dendritic cell precursor with an antigen.

5. The method of claim 1, wherein the oligodeoxynucleotide is modified to prevent degradation.

6. The method of claim 1, wherein the oligodeoxynucleotide has a phosphate backbone modification.

7. The method of claim 6, wherein the phosphate backbone modification is a phosphorothioate backbone modification.

8. The method of claim 1, wherein the oligodeoxynucleotide comprises 100 nucleotides or less.

9. The method claim 8, wherein the oligodeoxynucleotide comprises 50 nucleotides or less.

10. The method of claim 2, wherein the oligodeoxynucleotide comprises 18 to 30 nucleotides.

11. The method according to claim 1, wherein the dendritic cell precursor is a monocyte.

12. The method of claim 1, further comprising contacting the dendritic cell precursor with an agent that enhances dendritic cell maturation.

13. The method according to claim 12, wherein the agent is GM-CSF, IL-4, flt-3L or a combination thereof.

14. The method of claim 1, wherein the dendritic cell precursor is in vivo.

15. The method of claim 1, wherein the dendritic cell precursor is in vitro.

16. The method of claim 2, further comprising contacting the dendritic cell precursor with an antigen for a time sufficient to allow the antigen to be presented on the mature dendritic cell; thereby producing a mature antigen-presenting dendritic cell.

17. The method of claim 16, wherein the antigen is a protein, a polypeptide, a polysaccharide, a DNA molecule, a RNA molecule, a whole cell lysate, an apoptotic cell, or any combination thereof.

18. The method of claim 16, wherein the dendritic cell precursor is in vivo.

19. The method of claim 2, wherein the dendritic cell precursor is in vitro.

20. The method of claim 2, further comprising contacting the dendritic cell precursor with an agent that enhances dendritic cell maturation.

21. The method according to claim 20 wherein the agent is GM-CSF, IL-4, flt-3 ligand, or a combination thereof.

22. The method of claim 20, wherein the dendritic cell precursor is contacted with the oliogodeoxynucleotide and the antigen sequentially.

23. The method of claim 20, wherein the dendritic cell precursor is contacted with the oliogodeoxynucleotide and the antigen simultaneously.

24. The method of claim 3, wherein the dendritic cell precursor is in vivo.

25. The method of claim 3, wherein the dendritic cell precursor is in vitro.

26. A method for generating an activated T lymphocyte, comprising: producing a mature antigen presenting dendritic cell according to the method of claim 1; and contacting the mature antigen presenting dendritic cell with a T lymphocyte in vitro, thereby producing an activated T lymphocyte.

27. A method of producing an immune response against an antigen in a subject, comprising producing mature antigen presenting dendritic cells according the method of claim 1; contacting the mature antigen presenting dendritic cell with a T lymphocyte in vitro; and administering a therapeutically effective amount of the activated lymphocytes to the subject, thereby producing the immune response against the antigen in the subject.

28. The method of claim 1, wherein the dendritic cell precursor is not contacted with another mobilization agent.

29. The method of claim 1, wherein N is 6.

30. The method of claim 1, wherein Pu₁ Py₂ CpG Pu₃ Py₄ comprises phosphodiester bases.

31. The method of claim 30, wherein Pu₁ Py₂ CpG Pu₃ Py₄ are phosphodiester bases.

32. The method of claim 30, wherein X₁X₂X₃ and X₄X₅X₆(W)_M(G)_N comprise phosphodiester bases.

33. The method of claim 30, wherein X₁X₂X₃ comprises one or more phosphothioate bases.

34. The method of claim 30, wherein X₄X₅X₆(W)_M(G)_N comprises one or more phosphothioate bases.

35. The method of claim 2, wherein N is 6.

36. The method of claim 35, wherein Pu₁ Py₂ CpG Pu₃ Py₄ comprises phosphodiester bases.

37. The method of claim 36, wherein Pu₁ Py₂ CpG Pu₃ Py₄ are phosphodiester bases.

38. The method of claim 36, wherein X₁X₂X₃ and X₄X₅X₆(W)_M(G)_N comprise phosphodiester bases.

39. The method of claim 36, wherein X₁X₂X₃ comprises one or more phosphothioate bases.

40. The method of claim 36, wherein X₄X₅X₆(W)_M(G)_N comprises one or more phosphothioate bases.

41. The method of claim 2, wherein the oligodeoxynucleotide is modified to prevent degradation.

42. The method of claim 2, wherein the oligodeoxynucleotide has a phosphate backbone modification.

43. The method of claim 42, wherein the phosphate backbone modification is a phosphorothioate backbone modification.

44. The method of claim 2, wherein the oligodeoxynucleotide comprises 100 nucleotides or less.

45. The method of claim 44, wherein the oligodeoxynucleotide comprises 50 nucleotides or less.

46. The method of claim 2, wherein the dendritic cell precursor is a monocyte.

47. A method for generating an activated T lymphocyte, comprising: contacting a dendritic cell precursor with an effective amount of an oligodeoxynucleotide of at least about 16 nucleotides in length comprising a sequence represented by the following formula:
5′X₁X₂X₃Pu₁Py₂CpGPu₃Py₄X₄X₅X₆(W)_M(G)_N−3′ wherein the central CpG motif is unmethylated, Pu is a purine nucleotide, Py is a pyrimidine nucleotide, X and W are any nucleotide, M is any integer from 0 to 10, and N is any integer from 4 to 10, wherein X₁X₂X_{3 AND} X₄X₅X₆ are self complementary, thereby generating a mature antigen presenting dendritic cell; and contacting the mature antigen presenting dendritic cell with a T lymphocyte in vitro, thereby producing an activated T lymphocyte.

48. A method of producing an immune response against an antigen in a subject, comprising: contacting a dendritic cell precursor with an effective amount of an oligodeoxynucleotide of at least about 16 nucleotides in length comprising a sequence represented by the following formula:
5′X₁X₂X₃Pu₁Py₂CpGPu₃Py₄X₄X₅X₆(W)_M(G)_N−3′ wherein the central CpG motif is unmethylated, Pu is a purine nucleotide, Py is a pyrimidine nucleotide, X and W are any nucleotide, M is any integer from 0 to 10, and N is any integer from 4 to 10, wherein X₁X₂X_{3 AND} X₄X₅X₆ are self complementary, thereby generating a mature antigen presenting dendritic cell.

49. The method of claim 1, wherein the oligodeoxynucleotide comprises 18 to 30 nucleotides.

50. The method of claim 4, wherein the antigen is a protein, a polypeptide, a polysaccharide, a DNA molecule, a RNA molecule, a whole cell lysate, an apoptotic cell, or any combination thereof.

51. The method of claim 4, wherein the dendritic cell precursor is contacted with the oliogodeoxynucleotide and the antigen sequentially.

52. The method of claim 4, wherein the dendritic cell precursor is contacted with the oliogodeoxynucleotide and the antigen simultaneously.

53. The method of claim 3, wherein the oligodeoxynucleotide consists of the nucleic acid sequence GGTGCATCGATGCAGGGGGG (SEQ ID NO: 1) or the nucleotide sequence GGTGCACCGGTGCAGGGGGG (SEQ ID NO:2).

FIELD

This disclosure relates to dendritic cells, specifically to the methods of generating of mature dendritic cells using D type olidgodeoxynucleotides including a CpG motif.

BACKGROUND

Dendritic cells (DC) have been identified as a pivotal antigen presenting cell for initiation of an immune responses. It has been postulated that dendritic cells provide the basis for more effective immune responses, particularly for antigens wherein conventional vaccination is inadequate, or for use in producing a response to tumor antigens.

“Antigen presentation” is the set of events whereby cells fragment antigens into peptides, and then present these peptides in association with products of the major histocompatibility complex, (MHC). The MHC is a region of highly polymorphic genes whose products are expressed on the surfaces of a variety of cells. T cells recognize foreign antigens bound to only one specific class I or class II MHC molecule. The patterns of antigen association with either a class I or class II MHC molecule determines which T cells are stimulated.

T cells do not effectively respond to antigen unless the antigen is processed and presented to them by the appropriate antigen presenting cells (APC). The two major classes of antigen presenting cells are dendritic cells (DC) and macrophages. DC precursors migrate from bone marrow and circulate in the blood to specific sites in the body where they mature. This trafficking is directed by expression of chemokine receptors and adhesion molecules. Immature dendritic cells (DC) reside in the periphery and act as sentinels, detecting invasion by pathogenic microorganisms (Caetano, Immunity 14, 495-498, 2001). Exposure to certain agents trigger DC to differentiate and migrate to primary lymphoid organs where they present antigen to T cells and initiate a protective immune response (Banchereau, et al., Ann. Rev. Immunol. 18, 767-811, 2000; Banchereau & Steinman, Nature 392, 245-252, 1998). Tissue resident DC include Langerhans cells in skin, hepatic DC in the portal triads, mucosal DC and lung DC. Upon exposure to antigen and activation signals, the tissue resident DC are activated, and leave tissues to migrate via the afferent lymphatics to the T cell rich paracortex of the draining lymph nodes. The activated DC then secrete chemokines and cytokines involved in T cell homing and activation, and present processed antigen to T cells. In summary, dendritic cell precursors migrate to the primary lymphoid organs where they differentiate into mature dendritic cells.

Mature DC have a distinct morphology characterized by the presence of numerous membrane processes. These processes can take the form of dendrites, pseudopods or veils. DC are also characterized by the cell surface expression of large amounts of class II MHC antigens and the absence of lineage markers, including CD14 (monocyte), CD3 (T cell), CD19, 20, 24 (B cell), CD56 (natural killer), and CD66b (granulocyte). DC express a variety of adhesion and co-stimulatory molecules, e.g. CD80 and CD86, and molecules that regulate co-stimulation, such as CD40. The phenotype of DC varies with the stage of maturation and activation, where expression of adhesion molecules, MHC antigens and co-stimulatory molecules increases with maturation. Antibodies that preferentially stain mature DC include anti-CD83 and CMRF-44.

Activated DC are uniquely capable of processing and presenting antigens to naive T cells. The efficacy of DC in antigen presentation is widely acknowledged, but the clinical use of these cells is hampered by the fact that there are very few in any given organ. Animal studies demonstrate that mature DC can be generated ex vivo, loaded with antigen, and infused in vivo to trigger protective responses against tumors and pathogenic microorganisms (Fields et al., Proc. Natl. Acad. Sci 95: 9482-9487, 1998; Okada, H. et al. Int. J. Cancer 78: 196-201, 1998; Su et al., J. Exp. Med. 188: 809-818, 1998; DeMatos et al., J. Surg. Oncol., 68: 79-91, 1998; Zhu et al., J. Med. Primatol 29: 182-192, 2000). Large numbers of mature DC are required for this type of immunotherapy. These are typically generated by incubating human peripheral blood monocytes with GM-CSF plus IL-4 for one week, followed by monocyte-conditioned medium for 2-7 days (Gluckman et al., Cytokines Cell Mol Ther 3: 187-196, 1997; Chapuis et al., Eur. J. Immunol. 27: 431-441, 1997; Palucka et al., J. Immunol 160: 4587-4595, 1999). In human blood, for example, about 1% of the white cells are DC. While DC can process foreign antigens into peptides that immunologically active T cells can recognize, the low numbers of DC makes their therapeutic use very difficult. Thus, this process is not only lengthy and complex, but does not uniformly generate DC with full functional activity due to difficulties in standardizing the monocyte-conditioned medium (Tarte et al., Leukemia 14, 2182-2192, 2000; Verdijk et al., J. Immunol. 163, 57-61, 1999; Syme & Gluck, J. Hematother. Stem Cell Res. 10: 43-51, 2001). Thus, a need remains to generate mature dendritic cells in vitro.

SUMMARY

Novel methods for rapidly generating dendritic cells is disclosed herein. The methods include contacting a dendritic cell precursor with a D ODN to generate a mature dendritic cell. In one specific, non-limiting example, the method includes contacting the dendritic cell with an antigen. In another specific, non-limiting example, the method is a single step method wherein the D ODN is administered without other cytokines, such as GM-CSF and/or IL-4. These methods are of use both in vitro and in vivo.

In one embodiment, a method for generating a mature dendritic cell is disclosed herein. The method includes contacting a dendritic cell precursor with an effective amount of an oligodeoxynucleotide of at least about 16 nucleotides in length comprising a sequence represented by the following formula:
5′ X ₁ X ₂ X ₃ Pu ₁ Py ₂ CpG Pu ₃ Py ₄ X ₄ X ₅ X ₆ (W) _M (G) _N -3′
wherein the central CpG motif is unmethylated, Pu is a purine nucleotide, Py is a pyrimidine nucleotide, X and W are any nucleotide, M is any integer from 0 to 10, and N is any integer from 4 to 10, to generate a mature dendritic cell.

In another embodiment, a method is disclosed herein for producing a mature, antigen-presenting dendritic cell. The method includes contacting a dendritic cell precursor with an effective amount of an oligodeoxynucleotide of at least about 16 nucleotides in length comprising a sequence represented by the following formula:
5′ X ₁ X ₂ X ₃ Pu ₁ Py ₂ CpG Pu ₃ Py ₄ X ₄ X ₅ X ₆ (W) _M (G) _N -3′
wherein the central CpG motif is unmethylated, Pu is a purine nucleotide, Py is a pyrimidine nucleotide, X and W are any nucleotide, M is any integer from 0 to 10, and N is any integer from 4 to 10 to generate a mature dendritic cell. The method also includes contacting the mature dendritic cell with an antigen for a time sufficient to allow the antigen to be presented, thereby producing a mature antigen-presenting dendritic cell.

In a further embodiment, a single step method is disclosed for differentiating a dendritic precursor cell into a mature antigen presenting cell. The method includes contacting a dendritic cell precursor with an effective amount of an antigen and an oligodeoxynucleotide of at least about 16 nucleotides in length comprising a sequence represented by the following formula:
5′ X ₁ X ₂ X ₃ Pu ₁ Py ₂ CpG Pu ₃ Py ₄ X ⁴ X ₅ X ₆ (W) _M (G) _N -3′
wherein the central CpG motif is unmethylated, Pu is a purine nucleotide, Py is a pyrimidine nucleotide, X and W are any nucleotide, M is any integer from 0 to 10, and N is any integer from 4 to 10, thereby differentiating a mature antigen presenting cell.

The foregoing and other features and advantages will become more apparent from the following detailed description of several embodiments, which proceeds with reference to the accompanying figures.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a set of plots demonstrating that D ODN induce elutriated monocytes to differentiate into mature DC. Elutriated monocytes (95% pure) were incubated with 3 μM ODN for 24-96 h. Cells were fixed and stained for expression of CD83, CD86, CD80, CD40 and CD14 using fluorescence activated cell sorting. Results are representative of 5 independent experiments. The bottom panel provides a 600× magnification of Giemsa-stained cytospin preparations at each time point.

FIG. 2 is a set of plots and a bar graph showing that the contribution of pDC to D ODN induced monocyte differentiation. For the results shown in FIG. 2A, elutriated monocytes were depleted of, or enriched in. CD123 ^hi CD45RA ⁺ pDC. For the results shown in FIG. 2B, the pDC depleted monocytes were incubated for 48 h with 3 μM ODN and their maturation monitored by the appearance of CD83/CD86 ⁺ cells in the presence or absence of 5% pDC. The results shown in FIG. 2C demonstrate neutralizing anti-human IFNα Ab (10 μg/ml) significantly reduced DC maturation. FIG. 1D is a bar graph showing production of IFNα by pDC-enriched cultures stimulated with D ODN. Results are representative of 3 independent experiments.

FIG. 3 is a set of graphs showing that DC generated by D ODN treatment are active in mixed lymphocyte reaction. FIG. 3A is a set of line graphs of results obtained when elutriated monocytes were cultured in vitro for 2 days with 3 μM of control ODN (-∘-), D ODN (-▴-) or medium (-□-). These DC were mixed with monocyte-depleted peripheral blood lymphocytes from an allogeneic donor for 5 days and proliferation monitored. FIG. 3B is a bar graph of results obtained when supernatants from the 1:20 stimulator/responder cell MLR cultures were tested for IFNγ levels by ELISA ( medium; □ control ODN; ▪ D ODN). Data represent the mean ±SD of triplicate cultures from two donors, studied independently.

FIG. 4 is a bar graph demonstrating that DC generated by D ODN treatment can present tetanus toxoid to autologous T cells. PBMC from tetanus immune individuals were incubated with 3 μM of ODN for 2 days and then pulsed with tetanus toxoid for 4 h. After 12 h incubation with brefeldin A, the cells were fixed, permeabilized and stained with PE-conjugated anti-IFNγ plus FITC-conjugated anti-CD3. The mean ±SD of IFNγ producing CD3 ⁺ T cells from four independently studied individuals is shown. Note that there was no increase in the number of IL-4 producing cells in these cultures □ no antigen; ▪, tetanus toxoid).

FIG. 5 is a line graph of the comparative activity of DC generated by treating monocytes with D ODN vs GM-CSF plus IL-4.

Elutriated h