Treatment of a mouse model of collagen antibody-induced arthritis with human adipose-derived secretions

Sinead P. Blaber, Rebecca A. Webster, Edmond J. Breen, Graham Vesey, Benjamin R. Herbert

Australian Proteome Analysis Facility, Macquarie University, North Ryde, Australia.
Department of Chemistry and Biomolecular Sciences, Macquarie University, North Ryde, Australia&Regeneus Ltd., Gordon, Australia.
Department of Chemistry and Biomolecular Sciences, Macquarie University, North Ryde, Australia;&Regeneus Ltd., Gordon, Australia.
Regeneus Ltd., Gordon, Australia.

DOI: 10.4236/ojrm.2013.23012                

Abstract

The use of adipose-derived cells as a treatment for a variety of diseases is becoming increasingly common. These therapies include the use of cultured mesenchymal stem cells (MSCs) and freshly isolated stromal vascular fraction (SVF) alone, or in conjunction with other cells such as adipocytes. There is a substantial amount of literature published on the therapeutic properties of MSCs and their secretions as the main driver of their therapeutic effect. However, there is little data available on the therapeutic potential of secretions from SVF, either with or without adipocytes. We investigated the ability of secretions from human adipose SVF alone and the SVF co-cultured with adipocytes as a proxy for cell therapy, to ameliorate an inflammatory disorder. This ethics approved study involved the treatment of collagen antibody-induced arthritis (CAIA) in mice with secretions from SVF, SVF co-cultured with adipocytes, or a vehicle control via both intravenous (IV) and intramuscular (IM) routes. Treatment outcome was assessed by paw volume, ankle size and clinical arthritis score measurements. Serum samples were obtained following euthanasia and analysed for a panel of 32 mouse cytokines and growth factors. The dose and timing regime used for the IM administration of both human secretion mixtures did not significantly ameliorate arthritis in this model. The IV administration of SVF adipocyte co-culture secretions reduced the paw volume, and significantly reduced the ankle size and clinical arthritis score when compared to the IV vehicle control mice. This was a superior therapeutic effect than treatment with SVF secretions. Furthermore, treatment with SVF adipocyte coculture secretions resulted in a significant reduction in serum levels of key cytokines, IL-2 and VEGF, involved in the pathogenesis of rheumatoid arthritis. Therefore, the SVF cocultured with adipocytes is an attractive therapeutic for inflammatory conditions.

Keywords

Collagen Antibody-Induced Arthritis (CAIA); Stromal Vascular Fraction (SVF); Adipocytes; Co-Culture; Secretions; Cytokines; Growth Factors; Bio-Plex; Rheumatoid Arthritis

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Mahalatchimy, A., Rial-Sebbag, E., Tournay, V., et al. (2012) The legal landscape for advanced therapies: Material and institutional implementation of European Union rules in France and the United Kingdom. Journal of Law and Society, 39, 131-149. doi:10.1111/j.1467-6478.2012.00574.x
[2]	Nakagami, H., Maeda, K., Morishita, R., et al. (2005) Novel autologous cell therapy in ischemic limb disease through growth factor secretion by cultured adipose tissue-derived stromal cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 2542-2547. doi:10.1161/01.ATV.0000190701.92007.6d
[3]	Chopp, M. and Li, Y. (2002) Treatment of neural injury with marrow stromal cells. Lancet Neurology, 1, 92-100. doi:10.1016/S1474-4422(02)00040-6
[4]	Rehman, J., Traktuev, D., Li, J., et al. (2004) Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation, 109, 1292-1298. doi:10.1161/01.CIR.0000121425.42966.F1
[5]	Nishimura, S., Manabe, I., Nagasaki, M., et al. (2009) CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nature Medicine, 15, 914-920. doi:10.1038/nm.1964
[6]	Poggi, M., Jager, J., Paulmyer-Lacroix, O., et al. (2009) The inflammatory receptor CD40 is expressed on human adipocytes: Contribution to crosstalk between lymphocytes and adipocytes. Diabetologia, 52, 1152-1163. doi:10.1007/s00125-009-1267-1
[7]	Suganami, T., Nishida, J. and Ogawa, Y. (2005) A paracrine loop between adipocytes and macrophages aggravates inflammatory changes—Role of free fatty acids and tumor necrosis factor alpha. Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 2062-2068. doi:10.1161/01.ATV.0000183883.72263.13
[8]	Blaber, S.P., Webster, R.A., Hill, C.J., et al. (2012) Analysis of in vitro secretion profiles from adiposederived cell populations. Journal of Translational Medicine, 10, 172-188. doi:10.1186/1479-5876-10-172
[9]	Leonard, J.P., Sherman, M.L., Fisher, G.L., et al. (1997) Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-gamma production. Blood, 90, 2541-2548.
[10]	Vial, T. and Descotes, J. (1995) Immune-mediated side-effects of cytokines in humans. Toxicology, 105, 31-57. doi:10.1016/0300-483X(95)03124-X
[11]	Tayal, V. and Kalra, B.S. (2008) Cytokines and anti-cytokines as therapeutics—An update. European Journal of Pharmacology, 579, 1-12.
[12]	Gabay, C., Lamacchia, C. and Palmer, G. (2010) IL-1 pathways in inflammation and human diseases. Nature Reviews Rheumatology, 6, 232-241. doi:10.1038/nrrheum.2010.4
[13]	Asahara, T., Bauters, C., Zheng, L.P., et al. (1995) Synergistic effect of vascular endothelial growth factor and basic fibroblast growth factor on angiogenesis in vivo. Circulation, 92, 365-371. doi:10.1161/01.CIR.92.9.365
[14]	Cao, R., Brakenhielm, E., Pawliuk, R., et al. (2003) Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2. Nature Medicine, 9, 604-613. doi:10.1038/nm848
[15]	Meirelles Lda, S., Fontes, A.M., Covas, D.T., et al. (2009) Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine & Growth Factor Reviews, 20, 419-427. doi:10.1016/j.cytogfr.2009.10.002
[16]	Oh, J.Y., Kim, M.K., Shin, M.S., et al. (2008) The anti-inflammatory and anti-angiogenic role of mesenchymal stem cells in corneal wound healing following chemical injury. Stem Cells, 26, 1047-1055. doi:10.1634/stemcells.2007-0737
[17]	Timmers, L., Lim, S.K., Hoefer, I.E., et al. (2011) Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction. Stem Cell Research, 6, 206-214. doi:10.1016/j.scr.2011.01.001
[18]	Cho, Y.J., Song, H.S., Bhang, S., et al. (2012) Therapeutic effects of human adipose stem cell-conditioned medium on stroke. Journal of Neuroscience Research, 90, 1794-17802. doi:10.1002/jnr.23063
[19]	Williams, R.O., Inglis, J.J., Simelyte, E., et al. (2005) Analysing the effect of novel therapies on cytokine expression in experimental arthritis. International Journal of Experimental Pathology, 86, 267-278. doi:10.1111/j.0959-9673.2005.00443.x
[20]	Nandakumar, K.S. and Holmdahl, R. (2006) Antibody-induced arthritis: Disease mechanisms and genes involved at the effector phase of arthritis. Arthritis Research & Therapy, 8, 223. doi:10.1186/ar2089
[21]	Terato, K., Harper, D.S., Griffiths, M.M., et al. (1995) Collagen-induced arthritis in mice: Synergistic effect of E. coli lipopolysaccharide bypasses epitope specificity in the induction of arthritis with monoclonal antibodies to type II collagen. Autoimmunity, 22, 137-147. doi:10.3109/08916939508995311
[22]	Morris, C.J. (2003) Carrageenan-induced paw edema in the rat and mouse. Methods in Molecular Biology, 225, 115-121.
[23]	Khachigian, L.M. (2006) Collagen antibody-induced arthritis. Nature Protocols, 1, 2512-2516. doi:10.1038/nprot.2006.393
[24]	Schaller, J., Gerber, S., Kaempfer, U., et al. (2008) Human blood plasma proteins: Structure and function. John Wiley & Sons, West Sussex. doi:10.1002/9780470724378
[25]	Verhoef, C.M., van Roon, J.A., Vianen, M.E., et al. (1999) The immune suppressive effect of dexamethasone in rheumatoid arthritis is accompanied by upregulation of interleukin 10 and by differential changes in interferon gamma and interleukin 4 production. Annals of the Rheumatic Diseases, 58, 49-54. doi:10.1136/ard.58.1.49
[26]	Mosmann, T.R. and Sad, S. (1996) The expanding universe of T-cell subsets: Th1, Th2 and more. Immunology Today, 17, 138-146. doi:10.1016/0167-5699(96)80606-2
[27]	Wilbrink, B., Holewijn, M., Bijlsma, J.W., et al. (1993) Suppression of human cartilage proteoglycan synthesis by rheumatoid synovial fluid mononuclear cells activated with mycobacterial 60-kd heat-shock protein. Arthritis & Rheumatism, 36, 514-518. doi:10.1016/0167-5699(96)80606-2
[28]	Schulze-Koops, H., Lipsky, P.E., Kavanaugh, A.F., et al. (1995) Elevated Th1or Th0-like cytokine mRNA in peripheral circulation of patients with rheumatoid arthritis. Modulation by treatment with anti-ICAM-1 correlates with clinical benefit. The Journal of Immunology, 155, 5029-5037.
[29]	Dolhain, R.J.E.M., vander Heiden, A.N., terHaar, N.T., et al. (1996) Shift toward T lymphocytes with a T helper 1 cytokine-secretion profile in the joints of patients with rheumatoid arthritis. Arthritis & Rheumatism, 39, 1961-1969. doi:10.1002/art.1780391204
[30]	Agarwal, S.K. and Marshall, G.D. (2001) Dexamethasone promotes type 2 cytokine production primarily through inhibition of type 1 cytokines. Journal of Interferon & Cytokine Research, 21, 147-155. doi:10.1089/107999001750133159
[31]	Miossec, P. and van den Berg, W. (1997) Th1/Th2 cytokine balance in arthritis. Arthritis & Rheumatism, 40, 2105-2115. doi:10.1002/art.1780401203
[32]	Zappia, E., Casazza, S., Pedemonte, E., et al. (2005) Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood, 106, 1755-1761. doi:10.1182/blood-2005-04-1496
[33]	Gerdoni, E., Gallo, B., Casazza, S., et al. (2007) Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Annals of Neurology, 61, 219-227. doi:10.1002/ana.21076
[34]	Ichim, T.E., Harman, R.J., Min, W.P., et al. (2010) Autologous stromal vascular fraction cells: A tool for facilitating tolerance in rheumatic disease. Cellular Immunology, 264, 7-17. doi:10.1016/j.cellimm.2010.04.002
[35]	Nasef, A., Chapel, A., Mazurier, C., et al. (2007) Identification of IL-10 and TGF-beta transcripts involved in the inhibition of T-lymphocyte proliferation during cell contact with human mesenchymal stem cells. Gene Expression, 13, 217-226. doi:10.3727/000000006780666957
[36]	Li, H., Guo, Z., Jiang, X., et al. (2008) Mesenchymal stem cells alter migratory property of T and dendritic cells to delay the development of murine lethal acute graft-versus-host disease. Stem Cells, 26, 2531-2541. doi:10.1634/stemcells.2008-0146
[37]	Mokarizadeh, A., Delirezh, N., Morshedi, A., et al. (2012) Microvesicles derived from mesenchymal stem cells: Potent organelles for induction of tolerogenic signaling. Immunology Letters, 147, 47-54. doi:10.1016/j.imlet.2012.06.001
[38]	Deng, J., Zou, Z.M., Zhou, T.L., et al. (2011) Bone marrow mesenchymal stem cells can be mobilized into peripheral blood by G-CSF in vivo and integrate into traumatically injured cerebral tissue. Neurological Sciences, 32, 641-651. doi:10.1007/s10072-011-0608-2
[39]	Kokkonen, H., Soderstrom, I., Rocklov, J., et al. (2010) Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthritis & Rheumatism, 62, 383-391.
[40]	Syversen, S.W., Goll, G.L., Haavardsholm, E.A., et al. (2008) A high serum level of eotaxin (CCL 11) is associated with less radiographic progression in early rheumatoid arthritis patients. Arthritis Research & Therapy, 10, R28. doi:10.1186/ar2381
[41]	Feldmann, M. and Maini, R.N. (1999) The role of cytokines in the pathogenesis of rheumatoid arthritis. Rheumatology, 38, 3-7.
[42]	Thornton, S., Boivin, G.P., Kim, K.N., et al. (2000) Heterogeneous effects of IL-2 on collagen-induced arthritis. Journal of Immunology, 165, 1557-1563.
[43]	Morris, J.C. and Waldmann, T.A. (2000) Advances in interleukin 2 receptor targeted treatment. Annals of the Rheumatic Diseases, 59, 109-114. doi:10.1136/ard.59.suppl_1.i109
[44]	Brok, H.P.M., Tekoppele, J.M., Hakimi, J., et al. (2001) Prophylactic and therapeutic effects of a humanized monoclonal antibody against the IL-2 receptor (DACLIZUMAB) on collagen-induced arthritis (CIA) in rhesus monkeys. Clinical & Experimental Immunology, 124, 134-141. doi:10.1046/j.1365-2249.2001.01487.x
[45]	Paleolog, E.M. and Fava, R.A. (1998) Angiogenesis in rheumatoid arthritis: Implications for future therapeutic strategies. Springer Seminars in Immunopathology, 20, 73-94. doi:10.1007/BF00832000
[46]	Afuwape, A.O., Feldmann, M. and Paleolog, E.M. (2003) Adenoviral delivery of soluble VEGF receptor 1 (sFlt-1) abrogates disease activity in murine collagen-induced arthritis. Gene Therapy, 10, 1950-1960. doi:10.1038/sj.gt.3302104
[47]	Miotla, J., Maciewicz, R., Kendrew, J., et al. (2000) Treatment with soluble VEGF receptor reduces disease severity in murine collagen-induced arthritis. Laboratory Investigation, 80, 1195-1205. doi:10.1038/labinvest.3780127
[48]	Eppler, S.M., Combs, D.L., Henry, T.D., et al. (2002) A target-mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans. Clinical Pharmacology & Therapeutics, 72, 20-32. doi:10.1067/mcp.2002.126179
[49]	Pettersson, A., Nagy, J.A., Brown, L.F., et al. (2000) Heterogeneity of the angiogenic response induced in different normal adult tissues by vascular permeability factor/vascular endothelial growth factor. Laboratory Investigation, 80, 99-115. doi:10.1038/labinvest.3780013
[50]	Lalu, M.M., McIntyre, L., Pugliese, C., et al. (2012) Safety of cell therapy with mesenchymal stromal cells (SafeCell): A systematic review and meta-analysis of clinical trials. PLoS One, 7, e47559. doi:10.1371/journal.pone.0047559