Suppression of Murine Lupus by CD4+ and CD8+ Treg Cells Induced by T Cell-Targeted Nanoparticles Loaded With Interleukin-2 and Transforming Growth Factor β

Overview

Journal Arthritis Rheumatol

Publisher Wiley

Specialty Rheumatology

Date 2018 Nov 9

PMID 30407752

Citations 32

Authors

David A Horwitz

Sean Bickerton

Michael Koss

Tarek M Fahmy

Antonio La Cava

Affiliations

Soon will be listed here.

Abstract

Objective: To develop a nanoparticle (NP) platform that can expand both CD4+ and CD8+ Treg cells in vivo for the suppression of autoimmune responses in systemic lupus erythematosus (SLE).

Methods: Poly(lactic-co-glycolic acid) (PLGA) NPs encapsulating interleukin-2 (IL-2) and transforming growth factor β (TGFβ) were coated with anti-CD2/CD4 antibodies and administered to mice with lupus-like disease induced by the transfer of DBA/2 T cells into (C57BL/6 × DBA/2)F (BDF1) mice. The peripheral frequency of Treg cells was monitored ex vivo by flow cytometry. Disease progression was assessed by measuring serum anti-double-stranded DNA antibody levels by enzyme-linked immunosorbent assay. Kidney disease was defined as the presence of proteinuria or renal histopathologic features.

Results: Anti-CD2/CD4 antibody-coated, but not noncoated, NPs encapsulating IL-2 and TGFβ induced CD4+ and CD8+ FoxP3+ Treg cells in vitro. The optimal dosing regimen of NPs for expansion of CD4+ and CD8+ Treg cells was determined in in vivo studies in mice without lupus and then tested in BDF1 mice with lupus. The administration of anti-CD2/CD4 antibody-coated NPs encapsulating IL-2 and TGFβ resulted in the expansion of CD4+ and CD8+ Treg cells, a marked suppression of anti-DNA antibody production, and reduced renal disease.

Conclusion: This study shows for the first time that T cell-targeted PLGA NPs encapsulating IL-2 and TGFβ can expand both CD4+ and CD8+ Treg cells in vivo and suppress murine lupus. This approach, which enables the expansion of Treg cells in vivo and inhibits pathogenic immune responses in SLE, could represent a potential new therapeutic modality in autoimmune conditions characterized by impaired Treg cell function associated with IL-2 deficiency.

Citing Articles

Immune imbalance in Lupus Nephritis: The intersection of T-Cell and ferroptosis.

Fan Y, Ma K, Lin Y, Ren J, Peng H, Yuan L Front Immunol. 2024; 15:1520570.

PMID: 39726588 PMC: 11669548. DOI: 10.3389/fimmu.2024.1520570.

Recent Review on Biological Barriers and Host-Material Interfaces in Precision Drug Delivery: Advancement in Biomaterial Engineering for Better Treatment Therapies.

Deshmukh R, Sethi P, Singh B, Shiekmydeen J, Salave S, Patel R Pharmaceutics. 2024; 16(8).

PMID: 39204421 PMC: 11360117. DOI: 10.3390/pharmaceutics16081076.

Nanoparticles loaded with IL-2 and TGF-β promote transplantation tolerance to alloantigen.

Horwitz D, Wang J, Kim D, Kang C, Brion K, Bickerton S Front Immunol. 2024; 15:1429335.

PMID: 39131162 PMC: 11310063. DOI: 10.3389/fimmu.2024.1429335.

Biomaterial-enhanced treg cell immunotherapy: A promising approach for transplant medicine and autoimmune disease treatment.

Mashayekhi K, Khazaie K, Faubion Jr W, Kim G Bioact Mater. 2024; 37:269-298.

PMID: 38694761 PMC: 11061617. DOI: 10.1016/j.bioactmat.2024.03.030.

Bridging the gender gap in autoimmunity with T-cell-targeted biomaterials.

Ruiz A, Slaughter E, Kloxin A, Fromen C Curr Opin Biotechnol. 2024; 86:103075.

PMID: 38377884 PMC: 11578274. DOI: 10.1016/j.copbio.2024.103075.

References

Singh R, La Cava A, Wong M, Ebling F, Hahn B . CD8+ T cell-mediated suppression of autoimmunity in a murine lupus model of peptide-induced immune tolerance depends on Foxp3 expression. J Immunol. 2007; 178(12):7649-57. DOI: 10.4049/jimmunol.178.12.7649. View

Wong M, La Cava A . Lupus, the current therapeutic approaches. Drugs Today (Barc). 2011; 47(4):289-302. DOI: 10.1358/dot.2011.47.4.1583186. View

Ochando J, Yopp A, Yang Y, Garin A, Li Y, Boros P . Lymph node occupancy is required for the peripheral development of alloantigen-specific Foxp3+ regulatory T cells. J Immunol. 2005; 174(11):6993-7005. DOI: 10.4049/jimmunol.174.11.6993. View

Labowsky M, Fahmy T . Diffusive transfer between two intensely interacting cells with limited surface kinetics. Chem Eng Sci. 2012; 74:114-123. PMC: 3319135. DOI: 10.1016/j.ces.2012.02.001. View

Hahn B, Singh R, La Cava A, Ebling F . Tolerogenic treatment of lupus mice with consensus peptide induces Foxp3-expressing, apoptosis-resistant, TGFbeta-secreting CD8+ T cell suppressors. J Immunol. 2005; 175(11):7728-37. DOI: 10.4049/jimmunol.175.11.7728. View

Ferrera F, Hahn B, Rizzi M, Anderson M, FitzGerald J, Millo E . Protection against renal disease in (NZB x NZW)F(1) lupus-prone mice after somatic B cell gene vaccination with anti-DNA immunoglobulin consensus peptide. Arthritis Rheum. 2007; 56(6):1945-53. DOI: 10.1002/art.22700. View

Hunter Z, P McCarthy D, Yap W, Harp C, Getts D, Shea L . A biodegradable nanoparticle platform for the induction of antigen-specific immune tolerance for treatment of autoimmune disease. ACS Nano. 2014; 8(3):2148-60. PMC: 3990004. DOI: 10.1021/nn405033r. View

Maldonado R, LaMothe R, Ferrari J, Zhang A, Rossi R, Kolte P . Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance. Proc Natl Acad Sci U S A. 2014; 112(2):E156-65. PMC: 4299193. DOI: 10.1073/pnas.1408686111. View

Steenblock E, Fadel T, Labowsky M, Pober J, Fahmy T . An artificial antigen-presenting cell with paracrine delivery of IL-2 impacts the magnitude and direction of the T cell response. J Biol Chem. 2011; 286(40):34883-92. PMC: 3186438. DOI: 10.1074/jbc.M111.276329. View

10.

Scalapino K, Daikh D . Suppression of glomerulonephritis in NZB/NZW lupus prone mice by adoptive transfer of ex vivo expanded regulatory T cells. PLoS One. 2009; 4(6):e6031. PMC: 2696596. DOI: 10.1371/journal.pone.0006031. View

11.

Kang H, Michaels M, Berner B, Datta S . Very low-dose tolerance with nucleosomal peptides controls lupus and induces potent regulatory T cell subsets. J Immunol. 2005; 174(6):3247-55. DOI: 10.4049/jimmunol.174.6.3247. View

12.

GRAY J, Hirokawa M, Horwitz D . The role of transforming growth factor beta in the generation of suppression: an interaction between CD8+ T and NK cells. J Exp Med. 1994; 180(5):1937-42. PMC: 2191718. DOI: 10.1084/jem.180.5.1937. View

13.

Moulton V, Tsokos G . T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity. J Clin Invest. 2015; 125(6):2220-7. PMC: 4497749. DOI: 10.1172/JCI78087. View

14.

Zhang L, Bertucci A, Ramsey-Goldman R, Burt R, Datta S . Regulatory T cell (Treg) subsets return in patients with refractory lupus following stem cell transplantation, and TGF-beta-producing CD8+ Treg cells are associated with immunological remission of lupus. J Immunol. 2009; 183(10):6346-58. PMC: 2784684. DOI: 10.4049/jimmunol.0901773. View

15.

von Spee-Mayer C, Siegert E, Abdirama D, Rose A, Klaus A, Alexander T . Low-dose interleukin-2 selectively corrects regulatory T cell defects in patients with systemic lupus erythematosus. Ann Rheum Dis. 2015; 75(7):1407-15. DOI: 10.1136/annrheumdis-2015-207776. View

16.

Otomo K, Koga T, Mizui M, Yoshida N, Kriegel C, Bickerton S . Cutting Edge: Nanogel-Based Delivery of an Inhibitor of CaMK4 to CD4+ T Cells Suppresses Experimental Autoimmune Encephalomyelitis and Lupus-like Disease in Mice. J Immunol. 2015; 195(12):5533-7. PMC: 4670795. DOI: 10.4049/jimmunol.1501603. View

17.

Lan Q, Zhou X, Fan H, Chen M, Wang J, Ryffel B . Polyclonal CD4+Foxp3+ Treg cells induce TGFβ-dependent tolerogenic dendritic cells that suppress the murine lupus-like syndrome. J Mol Cell Biol. 2012; 4(6):409-19. PMC: 3523557. DOI: 10.1093/jmcb/mjs040. View

18.

GRAY J, Hirokawa M, Ohtsuka K, Horwitz D . Generation of an inhibitory circuit involving CD8+ T cells, IL-2, and NK cell-derived TGF-beta: contrasting effects of anti-CD2 and anti-CD3. J Immunol. 1998; 160(5):2248-54. View

19.

Park J, Gao W, Whiston R, Strom T, Metcalfe S, Fahmy T . Modulation of CD4+ T lymphocyte lineage outcomes with targeted, nanoparticle-mediated cytokine delivery. Mol Pharm. 2010; 8(1):143-52. PMC: 3040098. DOI: 10.1021/mp100203a. View

20.

Horwitz D, Pan S, Ou J, Wang J, Chen M, Gray J . Therapeutic polyclonal human CD8+ CD25+ Fox3+ TNFR2+ PD-L1+ regulatory cells induced ex-vivo. Clin Immunol. 2013; 149(3):450-63. PMC: 3941976. DOI: 10.1016/j.clim.2013.08.007. View