Vaccine Immunomodulation of Disease: Targeting the Treatment of Autoimmune Diseases

Main Article Content

Ken Steven Rosenthal Daniel H Zimmerman

Abstract

Autoimmune disease disrupts the normal immunological balance by promoting a perpetual cycle of innate/immune/inflammatory responses that continues due to the continued presence of antigen. The disease cycle is in turn amplified and regulated by cycles of antigen-specific T cell mediated immune responses. Removal of the stimuli or regulation of the disease drivers can stop the cycle to allow rebalancing and prevent the progression or chronicity of disease. As an alternative to the current treatments for autoimmune and inflammatory disease, which reduce, inhibit or eliminate the triggers, drivers or antigens, newer approaches stimulate regulatory responses, or inhibit or repurpose the effector/inflammatory responses to control the immune disease cycle. LEAPS (Ligand Epitope Antigen Presentation System) therapeutic vaccines for rheumatoid arthritis are presented as examples of therapies that elicit antigen specific T cell modulation of autoimmune and inflammatory responses to treat disease.

Article Details

How to Cite
ROSENTHAL, Ken Steven; ZIMMERMAN, Daniel H. Vaccine Immunomodulation of Disease: Targeting the Treatment of Autoimmune Diseases. Medical Research Archives, [S.l.], v. 10, n. 7, july 2022. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2910>. Date accessed: 08 aug. 2022. doi: https://doi.org/10.18103/mra.v10i7.2910.
Section
Research Articles

References

1. Rosenthal KS. Dealing with Garbage is the Immune System’s Main Job. MOJ Immunol.2017; 5(6): 00174. DOI:10.15406/moji.2017.05.00174 http://medcraveonline.com/MOJI/MOJI-05-00174.pdf
2. Rosenthal KS. Immune Monitoring of the body’s borders. AIMS Allergy and Immunol. 2018; 2(3): 148–164. DOI: 10.3934/Allergy.2018.3.148 http://www.aimspress.com/article/10.3934/Allergy.2018.3.148
3. Medzhitov R, Janeway Jr C. Innate immune recognition: Mechanisms and pathways. Immunol. Rev. 2000; 173: 89–97. doi: 10.1034/j.1600-065X.2000.917309.x;pmid: 10719670
4. Zimmerman DH, Carambula RE, Ciemielewski J, Rosenthal KS. Lessons from next generation influenza vaccines for inflammatory disease therapies. Int. Immunopharmacol. 2019; 74: 105729, doi:10.1016/j.intimp.2019.105729
5. Rosenthal KS, Zimmerman D. J-LEAPS vaccines elicit antigen specific Th1 responses by promoting maturation of type 1 dendritic cells (DC1). AIMS Allergy Immunol. 2017; 1: 89–100, doi:10.3934/Allergy.2017.2.89
6. Rosenthal KS, Mikecz K, Steiner III HL, Glant TT, Finnegan A, Carambula RE, Zimmerman DH. Rheumatoid arthritis vaccine therapies: perspectives and lessons from therapeutic ligand epitope antigen presentation system vaccines for models of rheumatoid arthritis. Expert Rev. Vaccines. 2015; 14: 891-908
7. Markovics A, Rosenthal KS, Mikecz K, Carambula RE, Ciemielewski JC, Zimmerman DH. Restoring the Balance between Pro-Inflammatory and Anti-Inflammatory Cytokines in the Treatment of Rheumatoid Arthritis: New Insights from Animal Models. Biomedicines. 2022; 10(1):44. https://doi.org/10.3390/biomedicines10010044
8. Yang D, Han Z, Oppenheim JJ. Alarmins and immunity. Immunol Rev. 2017;280(1):41-56. doi:10.1111/imr.12577
9. Welsh RM, Bahl K, Marshall HD, Urban SL. Type 1 interferons and antiviral CD8 T-cell responses. PLoS Pathog. 2012;8(1):e1002352. doi:10.1371/journal.ppat.1002352
10. Peiseler M, Kubes P. More friend than foe: the emerging role of neutrophils in tissue repair. J Clin Invest. 2019;129(7):2629-2639. https://doi.org/10.1172/JCI124616.
11. Lendeckel U, Venz S, Wolke C. Macrophages: shapes and functions. ChemTexts. 2022;8(2):12. doi:10.1007/s40828-022-00163-4
12. Eisenbarth, S.C. Dendritic cell subsets in T cell programming: location dictates function. Nat Rev Immunol. 2019;19: 89–103. https://doi.org/10.1038/s41577-018-0088-1
13. Birnbaum ME, Mendoza JL, Sethi DK, et al. Deconstructing the peptide-MHC specificity of T cell recognition. Cell. 2014; 157(5):1073-1087. doi:10.1016/j.cell.2014.03.047
14. Trowsdale J, Knight JC. Major histocompatibility complex genomics and human disease. Annu Rev Genomics Hum Genet. 2013;14:301-323. doi:10.1146/annurev-genom-091212-153455
15. Griffin DO, Rothstein TL. A small CD11b(+) human B1 cell subpopulation stimulates T cells and is expanded in lupus. J Exp Med. (2011) 208:2591–8. 10.1084/jem.20110978
16. Nowak UM, Newkirk MM: Rheumatoid Factors: Good or Bad for You? Int Arch Allergy Immunol 2005;138:180-188. doi: 10.1159/000088794
17. Cosmi L, Maggi L, Santarlasci V, Liotta F, Annunziato F. T Helper Cells Plasticity in Inflammation. Cytometry Part A. 2014; 85A: 36-42, DOI: 10.1002/cyto.a.22348
18. Dembic Z. Defending and integrating an organism by the immune system. Scand J Immunol. 2022;95(5):e13172. doi: 10.1111/sji.13172. PMID: 35416326
19. Zeng, H, Zhang, R., Jin, B, Chen L. Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance. Cell Mol Immunol. 2015; 12: 566–571 https://doi.org/10.1038/cmi.2015.44
20. Gol-Ara M, Jadidi-Niaragh F, Sadria R, Azizi G, Mirshafiey A. The role of different subsets of regulatory T cells in immunopathogenesis of rheumatoid arthritis. Arthritis. 2012; 2012:805875. doi:10.1155/2012/805875
21. Jonuleit H, Schmitt E. The Regulatory T Cell Family: Distinct Subsets and their Interrelations. J Immunol. 2003; 171 (12): 6323-6327; DOI: 10.4049/jimmunol.171.12.6323
22. Mellor, AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. 2004; 4: 762-774
23. Mbongue JC, Nicholas DA, Torrez TW, Kim N-S, Firek AF, Langridge WHR. The Role of Indoleamine 2, 3-Dioxygenase in Immune Suppression and Autoimmunity. Vaccines (Basel). 2015;3(3):703-729. doi:10.3390/vaccines3030703
24. DuPage M, Bluestone JA. Harnessing the plasticity of CD4 T cells to treat immune-mediated disease. Nat Rev Immunol. 2016; 16: 149-163
25. Suzuki M, Konya C, Goronzy JJ, Weyand CM. Inhibitory CD8+ T cells in autoimmune disease. Hum Immunol. 2008;69(11):781-9. doi: 10.1016/j.humimm.2008.08.283
26. Wurtz O, Bajénoff M, Guerder S. IL-4-mediated inhibition of IFN-gamma production by CD4+ T cells proceeds by several developmentally regulated mechanisms. Int Immunol. 2004;16(3):501-8. doi: 10.1093/intimm/dxh050.
27. Ria F, Penna G, Adorini L. Th1 cells induce and Th2 inhibit antigen-dependent IL-12 secretion by dendritic cells. Eur J Immunol. 1998;28(6):2003-16. doi: 10.1002/(SICI)1521-4141(199806)28:06<2003::AID-IMMU2003>3.0.CO;2-S
28. Mitchell, R.E., Hassan, M., Burton, B.R. et al. IL-4 enhances IL-10 production in Th1 cells: implications for Th1 and Th2 regulation. Sci Rep 2017; 7: 11315 https://doi.org/10.1038/s41598-017-11803-y
29. Kelchtermans H, Billiau A, Matthys P. How interferon-γ keeps autoimmune diseases in check. Trends in Immunology. 2008;29 (10): 479-486 https://doi.org/10.1016/j.it.2008.07.002
30. Markovics A, Zimmerman DH, Mikecz K, Rosenthal KS. Suppression of Arthritis by Immunomodulatory LEAPS Peptide Vaccines in Animal Models of Rheumatoid Arthritis. Int. J. Drug Dev. Res. 2021; 13: 9502
31. Fulop T, Larbi A, Pawelec G, et al. Immunology of Aging: the Birth of Inflammaging. Clin Rev Allergy Immunol. 2021;1-14. doi:10.1007/s12016-021-08899-6
32. Feehan J, Tripodi N, Apostolopoulos V. The twilight of the immune system: The impact of immunosenescence in aging. Maturitas. 2021;147:7-13 doi:10.1016/j.maturitas.2021.02.006
33. Wucherpfennig KW, Strominger JL. Selective binding of self peptides to disease-associated major histocompatibility complex (MHC) molecules: a mechanism for MHC-linked susceptibility to human autoimmune diseases. J Exp Med. 1995; 181: 1597-1601
34. Benoist C, Mathis D. Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry? Nat Immunol. 2001;2:797–801
35. Wucherpfennig KW, Strominger JL. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell. 1995;80:695–705
36. Lünemann JD, Jelcić I, Roberts S, et al. EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-gamma and IL-2. J Exp Med. 2008;205(8):1763-1773. doi:10.1084/jem.20072397
37. Powell AM, Black MM. Epitope spreading: protection from pathogens, but propagation of autoimmunity? Clin Exp Dermatol. 2001 Jul;26(5):427-33. doi: 10.1046/j.1365-2230.2001.00852.x
38. Goronzy, J., Weyand, C. Understanding immunosenescence to improve responses to vaccines. Nat Immunol. 2013; 14: 428–436. https://doi.org/10.1038/ni.2588
39. Smolen, J., Aletaha, D., Barton, A. et al. Rheumatoid arthritis. Nat. Rev. Dis. Prim. 2018; 4: 1–23, doi:10.1038/nrdp.2018.1
40. Weyand, C.M., Goronzy, J.J. The immunology of rheumatoid arthritis. Nat Immunol 2021; 22:10–18. https://doi.org/10.1038/s41590-020-00816-x
41. Stamnaes J, Sollid LM. Celiac disease: Autoimmunity in response to food antigen. Semin Immunol. 2015;27(5):343-52. doi: 10.1016/j.smim.2015.11.001.
42. Kawasaki E. Type 1 diabetes and autoimmunity. Clin Pediatr Endocrinol. 2014;23(4):99-105. doi:10.1297/cpe.23.99
43. Lutterotti A, Hayward-Koennecke H, Sospedra M, Martin R. Antigen-Specific Immune Tolerance in Multiple Sclerosis-Promising Approaches and How to Bring Them to Patients. Front Immunol. 2021;12:640935. doi:10.3389/fimmu.2021.640935
44. Dalaker M, Jacobsen T, Lysvand H, Iversen OJ. Expression of the psoriasis-associated antigen, Pso p27, is inhibited by cyclosporin A. Acta Derm Venereol. 1999 Jul;79(4):281-4. doi: 10.1080/000155599750010661
45. Iversen OJ, Lysvand H, Slupphaug G. Pso p27, a SERPINB3/B4-derived protein, is most likely a common autoantigen in chronic inflammatory diseases. Clin Immunol. 2017 Jan;174:10-17. doi: 10.1016/j.clim.2016.11.006
46. Lodes MJ, Cong Y, Elson CO, et al. Bacterial flagellin is a dominant antigen in Crohn disease. J Clin Invest. 2004;113(9):1296-1306. doi:10.1172/JCI20295
47. Mewar D, Wilson AG. Autoantibodies in rheumatoid arthritis: a review. Biomed Pharmacother 2001; 60: 648–655
48. Doyle HA, Mamula MJ. Autoantigenesis: the evolution of protein modifications in autoimmune disease. Curr. Opin. Immunol. 2012; 24: 112–118. doi:https://doi.org/10.1016/j.coi.2011.12.003
49. Mastrangelo A, Colasanti T, Barbati C, et al. The Role of Posttranslational Protein Modifications in Rheumatological Diseases: Focus on Rheumatoid Arthritis. J. Immunol. Res. 2015; 2015: article ID 712490. doi:10.1155/2015/712490
50. Spinelli FR, Pecani A, Conti F, et al. Post-translational modifications in rheumatoid arthritis and atherosclerosis: Focus on citrullination and carbamylation. J. Int. Med. Res. 2016; 44: 81–84. doi:10.1177/0300060515593258
51. Burska AN, Hunt L, Boissinot M, et al. Autoantibodies to posttranslational modifications in rheumatoid arthritis. Mediators Inflamm. 2014; 2014: Article ID 492873. doi:10.1155/2014/492873
52. van Roon JA, van Roy JL, Duits A, Lafeber FP, Bijlsma JW. Proinflammatory cytokine production and cartilage damage due to rheumatoid synovial T helper-1 activation is inhibited by interleukin-4. Ann Rheum Dis. 1995; 54: 836-840. DOI 10.1136/ard.54.10.836.
53. Kotake S, Yago T, Kobashigawa T, Nanke Y. The Plasticity of Th17 Cells in the Pathogenesis of Rheumatoid Arthritis. J Clin Med. 2017; 6(7):67. https://doi.org/10.3390/jcm6070067
54. Davis DH. Autoimmune disease: A role for new anti-viral therapies? Autoimmunity Rev. 2011;11(2):88-97.https://doi.org/10.1016/j.autrev.2011.08.005
55. Meier FMP, Frerix M,Hermann W, Müller-Ladner U. Current immunotherapy in rheumatoid arthritis. Immunotherapy. 2013; 5: https://doi.org/10.2217/imt.13.94
56. Senolt L. Emerging therapies in rheumatoid arthritis: focus on monoclonal antibodies. F1000Res. 2019 Aug 30;8:F1000 Faculty Rev-1549. doi: 10.12688/f1000research.18688.1
57. Bartlett H, Million R. Targeting the IL-17–TH17 pathway. Nat Rev Drug Discov.2015; 14: 11–12. https://doi.org/10.1038/nrd4518
58. O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med. 2013; 368: 161–70, doi:10.1056/NEJMra1202117
59. Harigai M, Honda S. Selectivity of Janus Kinase Inhibitors in Rheumatoid Arthritis and Other Immune-Mediated Inflammatory Diseases: Is Expectation the Root of All Headache? Drugs 2020; 80: 1183–1201, doi:10.1007/s40265-020-01349-1.
60. Lin CM, Cooles FA, Isaacs JD. Basic Mechanisms of JAK Inhibition. Mediterr. J. Rheumatol. 2020; 31: 100, doi:10.31138/mjr.31.1.100
61. Zarrin AA, Bao K, Lupardus P, Vucic D. Kinase inhibition in autoimmunity and inflammation. Nat. Rev. Drug Discov. 2021; 20: 39–63, doi:10.1038/s41573-020-0082-8
62. Mok CC. Rituximab for the treatment of rheumatoid arthritis: an update. Drug Des Devel Ther. 2013;8:87-100. Published 2013 Dec 27. doi:10.2147/DDDT.S41645
63. Fugger L, Jensen LT, Rossjohn J. Challenges, Progress, and Prospects of Developing Therapies to Treat Autoimmune Diseases. Cell 181; 2020:63-80. https://doi.org/10.1016/j.cell.2020.03.007
64. Sharma A, Rudra D. Regulatory T cells as therapeutic targets and mediators. Intl Rev Immunol. 2019; 38:183-r203. DOI 10.1080/088301:85.2019.1621310
65. Essensten JH, Wofsy D, Bluestone JA. Regulatory T cells as therapeutic targets in rheumatoid arthritis. Nat Rev Rheumatol. 2009;5:560-565 doi:10.1.1038/nrrheum.2009.183
66. Serra, P., Santamaria, P. Antigen-specific therapeutic approaches for autoimmunity. Nat Biotechnol. 2019; 37:238–251. https://doi.org/10.1038/s41587-019-0015-4
67. Hou J, Schindler U, Henzel WJ, Ho TC, Brasseur M, McKnight SL. An interleukin-4-induced transcription factor: IL-4 Stat. Science. 1994;265(5179):1701-6. doi: 10.1126/science.8085155. PMID: 8085155.
68. Couper KN, Blount DG, Riley EM. IL-10: The Master Regulator of Immunity to Infection. J Immunol. 2008; 180 (9): 5771-5777 DOI: https://doi.org/10.4049/jimmunol.180.9.5771
69. Saxena A, Khosraviani S, Noel S, Mohan D, Donner T, Hamad AR. Interleukin-10 paradox: A potent immunoregulatory cytokine that has been difficult to harness for immunotherapy. Cytokine. 2015;74(1):27-34. doi:10.1016/j.cyto.2014.10.031
70. Kelchtermans H, Billiau A, Matthys P. How interferon-γ keeps autoimmune diseases in check. Trends in Immunology. 2008; 29(10): 479-486 https://doi.org/10.1016/j.it.2008.07.002.
71. Eggenhuizen PJ, Ng BH, Ooi JD. Treg Enhancing Therapies to Treat Autoimmune Diseases. Int J Molec Sci. 2020; 21(19):7015. https://doi.org/10.3390/ijms21197015
72. Mosanya CH, Isaacs JD. Tolerising cellular therapies: what is their promise for autoimmune disease? Ann Rheum Dis. 2019;78:297–310. doi: 10.1136/annrheumdis-2018-214024
73. Zhang N, Nandakumar KS. Recent advances in the development of vaccines for chronic inflammatory autoimmune diseases. Vaccine.2018; 36(23): 3208-3220. https://doi.org/10.1016/j.vaccine.2018.04.062
74. Sharma A, Rudra D. Regulatory T cells as therapeutic targets and mediators. Int Rev Immunol. 2019; 38(5): 183-203 DOI: 10.1080/08830185.2019.1621310
75. Ding T, Niu H, Zhao X, Gao C, Li X, Wang C. T-Follicular Regulatory Cells: Potential Therapeutic Targets in Rheumatoid Arthritis. Frontiers in Immunology.2019; 10. DOI=10.3389/fimmu.2019.02709 https://www.frontiersin.org/article/10.3389/fimmu.2019.02709
76. Schijns V, Fernández-Tejada A, Barjaktarović Z,et al. Modulation of immune responses using adjuvants to facilitate therapeutic vaccination. Immunol Rev. 2020; 296: 169– 190. https://doi.org/10.1111/imr.12889
77. Keijzer C, van der Zee R, van Eden W, Broere F. Treg Inducing Adjuvants for Therapeutic Vaccination Against Chronic Inflammatory Diseases. Frontiers in Immunology. 2013; 4. https://www.frontiersin.org/article/10.3389/fimmu.2013.00245 DOI=10.3389/fimmu.2013.00245
78. Hunter Z, McCarthy DP, Yap WT, et al. A Biodegradable Nanoparticle Platform for the Induction of Antigen-Specific Immune Tolerance for Treatment of Autoimmune Disease. ACS Nano. 2014; 8(3): 2148–2160. https://doi.org/10.1021/nn405033r
79. Van Brussel I, Lee WP, Rombouts M, et al. Tolerogenic dendritic cell vaccines to treat autoimmune diseases: Can the unattainable dream turn into reality? Autoimmunity Rev. 2014; 13(2):138-150. https://doi.org/10.1016/j.autrev.2013.09.008.
80. Faria AM, Weiner HL. Oral tolerance. Immunol Rev. 2005;206:232-59. doi: 10.1111/j.0105-2896.2005.00280.x. PMID: 16048553; PMCID: PMC3076704.
81. Pinheiro-Rosa N, Torres L, de Almeida Oliveira M, et al. Oral tolerance as antigen-specific immunotherapy. Immunotherapy Advances, 2021; 1 (1) ltab017, https://doi.org/10.1093/immadv/ltab017
82. Husseiny MI, Dua W, Mbongue J, Lenz A, Rawson J, Kandeel F, Ferreria K. Factors affecting Salmonella-based combination immunotherapy for prevention of type 1 diabetes in non-obese diabetic mice. Vaccine.2018; 36(52): 8008-8018. ISSN 0264-410X, https://doi.org/10.1016/j.vaccine.2018.10.101.
83. Larsson HE, Lernmark A. Vaccination against type 1 diabetes. J Intern Med. 2011; 269: 626–635. https://doi.org/10.1111/j.1365-2796.2011.02386.x
84. Husseiny MI, Rawson J, Kaye A, et al. An oral vaccine for type 1 diabetes based on live attenuated Salmonella. Vaccine. 2014 Apr 25;32(20):2300-7. doi: 10.1016/j.vaccine.2014.02.070.
85. Nicholas D, Odumosu O, Langridge WH. Autoantigen based vaccines for type 1 diabetes. Discov Med. 2011 Apr;11(59):293-301. PMID: 21524383; PMCID: PMC6474774.
86. Willekens B, Cools N. Beyond the Magic Bullet: Current Progress of Therapeutic Vaccination in Multiple Sclerosis. CNS Drugs.2018; 32:401–410 https://doi.org/10.1007/s40263-018-0518-4
87. Di Sabatino A, Lenti MV, Corazza GR, Gianfrani C. Vaccine Immunotherapy for Celiac Disease. Frontiers in Medicine. 2018; https://www.frontiersin.org/article/10.3389/fmed.2018.00187 DOI=10.3389/fmed.2018.00187
88. Moreland LW, Morgan EE, Adamson TC 3rd, et al. T Cell Receptor Peptide Vaccination in Rheumatoid Arthritis. Arthritis & Rheumatism.1998; 31:1919-1929. doi: 10.1002/1529-0131(199811)41:11<1919::AID-ART5>3.0.CO;2-1
89. Kim J, Chun K, McGowan J, Chakravarti R. 14-3-3ζ: A suppressor of inflammatory arthritis. Proc Nat Acad Sci (USA). 2021;118(34) https://doi.org/10.1073/pnas.2025257118
90. Ichim TE, Zheng X, Suzuki M, et al., Antigen-specific therapy of rheumatoid arthritis. Expert Opin. Biol. Ther. 8, 191–199 (2008). doi: 10.1517/14712598.8.2.191
91. Thomas R. Dendritic cells and the promise of antigen-specific therapy in rheumatoid arthritis. Arthritis Res. Ther. 2013; 15: 204 doi: 10.1186/ar4130
92. Khan, S., Greenberg, J. & Bhardwaj, N. Dendritic cells as targets for therapy in rheumatoid arthritis. Nat Rev Rheumatol. 2009; 5: 566–571 (2009). https://doi.org/10.1038/nrrheum.2009.185
93. Rosenthal KS, Taylor P, Zimmerman DH. J-LEAPS peptide and LEAPS dendritic cell vaccines. Microb. Biotechnol. 2012; 5: 203–13, doi:10.1111/j.1751-7915.2011.00278.x.
94. Mikecz K, Glant TT, Markovics A, et al. An epitope-specific DerG-PG70 LEAPS vaccine modulates T cell responses and suppresses arthritis progression in two related murine models of rheumatoid arthritis. Vaccine. 2017; 35: 4048–4056, doi:10.1016/j.vaccine.2017.05.009.
95. Zimmerman DH, Mikecz K, Markovics A, et al. Vaccination by Two DerG LEAPS Conjugates Incorporating Distinct Proteoglycan (PG, Aggrecan) Epitopes Provides Therapy by Different Immune Mechanisms in a Mouse Model of Rheumatoid Arthritis. Vaccines. 2021; 9: 448, https://doi.org/10.3390/vaccines9050448
96. Glant TT, Mikecz K, Arzoumanian A, Poole AR. Proteoglycan-induced arthritis in BALB/c mice. Clinical features and histopathology. Arthritis Rheum. 1987, 30, 201–12. DOI: 10.1002/art.1780300211
97. Glant TT, Radacs M, Nagyeri G, et al. Proteoglycan-induced arthritis and recombinant human proteoglycan aggrecan G1 domain-induced arthritis in BALB/c mice resembling two subtypes of rheumatoid arthritis. Arthritis Rheum. 2011;63: 1312–21, doi:10.1002/art.30261
98. Rodeghero R, Cao Y, Olalekan SA, Iwakua Y, Glant TT, Finnegan A. Location of CD4+ T cell priming regulates the differentiation of Th1 and Th17 cells and their contribution to arthritis. J. Immunol. 2013; 190: 5423–35, doi:10.4049/jimmunol.1203045
99. Taylor PR, Koski GK, Paustian CC, et al. J-LEAPS vaccines initiate murine Th1 responses by activating dendritic cells. Vaccine 2010; 28: 5533–42. doi:10.1016/j.vaccine.2010.06.043
100. Taylor PR, Paustian CC, Koski GK, Zimmerman DH, Rosenthal KS. 2010. Maturation of dendritic cell precursors into IL12 producing DCs by J-LEAPS Immunogens. Cellular Immunology. 2010; 262: 1-5. https://doi.org/10.1016/j.cellimm.2010.01.003
101. Goel N, Rong Q, Zimmerman DH, Rosenthal KS. A L.E.A.P.S. heteroconjugate vaccine containing a T cell epitope from HSV-1 glycoprotein D elicits Th1 responses and protection. Vaccine. 2003; 21: 4410–20. doi:10.1016/S0264-410X(03)00429-8.
102. Zimmerman DH, Taylor P, Bendele A, et al. CEL-2000: A therapeutic vaccine for rheumatoid arthritis arrests disease development and alters serum cytokine/chemokine patterns in the bovine collagen type II induced arthritis in the DBA mouse model. Int Immunopharmacol. 2010; 10: 412–21, doi:10.1016/j.intimp.2009.12.016.
103. Cihakova D, Barin JG, Baldeviano GC, et al. L.E.A.P.S. heteroconjugate is able to prevent and treat experimental autoimmune myocarditis by altering trafficking of autoaggressive cells to the heart. Int Immunopharmacol. 2008 May;8(5):624-33. doi: 10.1016/j.intimp.2008.01.004
104. Rosenthal KS, Mao HW, Horne WI, Wright C, Zimmerman, DH. Immunization with a LEAPS heteroconjugate containing a CTL epitope and a peptide from beta-2-microglobulin elicits a protective and DTH response to herpes simplex virus type 1. Vaccine. 1999; 17: 535–42. DOI: 10.1016/s0264-410x(98)00231-x
105. Rosenthal KS, Stone S, Koski G, Zimmerman GK. LEAPS Vaccine Incorporating HER-2/neu Epitope Elicits Protection That Prevents and Limits Tumor Growth and Spread of Breast Cancer in a Mouse Model. J. Immunol. Res. 2017; 2017: 1–8, doi:10.1155/2017/3613505.
106. Boonnak K, Vogel L, Orandle M, Zimmerman DH, Talor E, Subbarao K. Antigen-activated dendritic cells ameliorate influenza A infections. J Clin Invest. 2013; 123: 2850-2861. doi: 10.1172/JCI67550
107. Yang D, Han Z, Oppenheim JJ. Alarmins and immunity. Immunol Rev. 2017;280(1):41-56. DOI: 10.1111/imr.12577