Subscribe to RSS
DOI: 10.1055/s-0030-1256382
© Georg Thieme Verlag KG Stuttgart · New York
Low dose endoluminal photodynamic therapy improves murine T cell-mediated colitis
Publication History
submitted 30 September 2008
accepted after revision 31 January 2011
Publication Date:
27 May 2011 (online)

Background and study aims: Low dose photodynamic therapy (LDPDT) may modify the mucosal immune response and may thus provide a therapy for Crohn’s disease. We evaluated the efficacy and safety of this technique in a murine T cell-mediated colitis model.
Methods: The safety of LDPDT was first tested in BALB/c mice. Naïve T cells were used to induce colitis in mice with severe combined immunodeficiency, which were followed up endoscopically, and a murine endoscopic index of colitis (MEIC) was developed. The efficacy of LDPDT (10 J/cm2; delta-aminolevulinic acid, 15 mg/kg bodyweight) was then tested on mice with moderate colitis, while a disease control group received no treatment. The MEIC, weight, length, and histology of the colon, cytokine expression indices, number of mucosal CD4+ T cells, percentage of apoptotic CD4+ T cells, body weight, and systemic side effects were evaluated.
Results: LDPDT improved the MEIC (P = 0.011) and the histological score (P = 0.025), diminished the expression indices of the proinflammatory cytokines, interleukin-6 (P = 0.042), interleukin-17 (P = 0.029), and interferon-gamma (P = 0.014), decreased the number of mucosal CD4+ T cells, and increased the percentage of apoptotic CD4+ T cells compared with the disease control group. No local or systemic side effects occurred.
Conclusion: LDPDT improves murine T cell-mediated colitis, decreases the proinflammatory cytokines interleukin-6, interleukin-17, and interferon-gamma, and decreases the number of CD4+ T cells. No adverse events were observed. Therefore, this technique is now being evaluated in patients with inflammatory bowel disease.
References
- 1 Kucharzik T, Maaser C, Lügering A et al. Recent understanding of IBD pathogenesis: implications for future therapies. Inflamm Bowel Dis. 2006; 12 1068-1083
- 2 Young Y, Abreu M T. Advances in the pathogenesis of inflammatory bowel disease. Curr Gastroenterol Rep. 2006; 8 470-477
- 3 Strober W, Fuss I, Mannon P. The fundamental basis of inflammatory bowel disease. J Clin Invest. 2007; 117 514-521
- 4 Xavier R J, Podolsky D K. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007; 448 427-434
- 5 Iwakura Y, Ishigame H. The IL-23/IL-17 axis in inflammation. J Clin Invest. 2006; 116 1218-1222
- 6 Yen D, Cheung J, Scheerens H et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006; 116 1310-1316
- 7 Duerr R H, Taylor K D, Brant S R et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006; 314 1461-1463
- 8 Sturm A, Fiocchi C. Life and death in the gut: more killing, less Crohn’s. Gut. 2002; 50 148-149
- 9 Danese S, Sans M, de la Motte C et al. Angiogenesis as a novel component of inflammatory bowel disease pathogenesis. Gastroenterology. 2006; 130 2060-2073
- 10 Targan S R. Current limitations of IBD treatment: where do we go from here?. Ann NY Acad Sci. 2006; 1072 1-8
- 11 Colombel J F, Sandborn W J, Rutgeerts P et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology. 2007; 132 52-65
- 12 Hanauer S B, Feagan B G, Lichtenstein G R et al. ACCENT I Study Group. Maintenance infliximab for Crohn’s disease: The ACCENT I randomized trial. Lancet. 2002; 359 1541-1549
- 13 Schreiber S, Khaliq-Kareemi M, Lawrence I C et al. PRECISE 2 Study Investigators. Maintenance therapy with certolizumab pegol for Crohn’s disease. NEJM. 2007; 357 239-250
- 14 Baert F, Norman M, Vermeire S et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. NEJM. 2003; 348 601-608
- 15 Aksamit A J. Review of progressive multifocal leukoencephalopathy and natalizumab. Neurologist. 2006; 12 293-298
- 16 Rychly D J, DiPiro J T. Infection associated with tumor necrosis factor-alpha antagonists. Pharmacotherapy. 2005; 25 1181-1192
- 17 Mackey A C, Green L, Liang L C et al. Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2007; 44 265-267
- 18 Ortner M, Caca K, Berr F et al. Photodynamic therapy for non-resectable cholangiocarcinoma: a randomized prospective study. Gastroenterology. 2003; 125 1355-1363
- 19 Eleouet S, Carre J, Vonarx V et al. Delta-aminolevulinic acid-induced fluorescence in normal human lymphocytes. J Photochem Photobiol B. 1997; 41 22-29
- 20 Hunt D W, Jiang H, Granville D J et al. Consequences of the photodynamic treatment of resting and activated peripheral T lymphocytes. Immunopharmacology. 1999; 41 31-44
- 21 Jiang H, Granville D J, North J R et al. Selective action of the photosensitizer QLT0074 on activated human T lymphocytes. Photochem Photobiol. 2002; 76 224-231
- 22 Hryhorenko E A, Oseroff A R, Morgan J et al. Deletion of alloantigen-activated cells by aminolevulinic acid-based photodynamic therapy. Photochem Photobiol. 1999; 69 560-565
- 23 Bissonnette R, Tremblay J F, Juzenas P et al. Systemic photodynamic therapy with aminolevulinic acid induces apoptosis in lesional T-lymphocytes of psoriatic plaques. J Invest Dermatol. 2002; 119 77-83
- 24 Hunt D W, Chan A H. Influence of photodynamic therapy on immunological aspects of disease – an update. Expert Opin Investig Drugs. 2000; 9 807-817
- 25 Musser D A, Oseroff A R. Characteristics of the immunosuppression induced by cutaneous photodynamic therapy: persistence, antigen specificity and cell type involved. Photochem Photobiol. 2001; 73 518-524
- 26 Simkin G O, Tao J S, Lervy J G et al. IL-10 contributes to the inhibition of contact hypersensitivity in mice treated with photodynamic therapy. J Immunol. 2000; 164 2457-2462
- 27 Jori G. Photodynamic therapy of microbial infections: state of the art and perspectives. J Environ Pathol Toxicol Oncol. 2006; 25 505-519
- 28 Pegaz B, Debefve E, Borle F et al. Preclinical evaluation of a novel water-soluble chlorin E6 derivate (BLC 1010) as photosensitizer for the closure of the neovessels. Photochem Photobiol. 2005; 81 1505-1510
- 29 Boehncke W H, Elshorst-Schmidt T, Kaufmann R. Systemic photodynamic therapy is a safe and effective treatment of psoriasis. Arch Dermatol. 2000; 136 271-272
- 30 Funke B, Jungel A, Schastak S et al. Transdermal photodynamic therapy – a treatment option for rheumatoid destruction of small joints?. Lasers Surg Med. 2006; 38 866-874
- 31 Ratkay L G, Chowdhary R K, Iamaroon A et al. Amelioration of antigen-induced arthritis in rabbits by induction of apoptosis of inflammatory cells with local application of transdermal photodynamic therapy. Arthritis Rheum. 1998; 41 525-534
- 32 Chowdhary R K, Ratkay L G, Neyndorff H C et al. The use of transcutaneous photodynamic therapy in the prevention of adjuvant-enhanced arthritis in MRL/lpr mice. Clin Immunol Immunopathol. 1994; 72 255-263
- 33 Ratkay L G, Chowdhary R K, Neyendorff H C et al. Photodynamic therapy: A comparison with other immunomodulatory treatments of adjuvant-enhanced arthritis in MRL-lpr mice. Clin Exp Immunol. 1994; 95 373-377
- 34 Hunt D W, Jiang H, Granville D J et al. Consequence of the photodynamic treatment of resting and activated peripheral T lymphocytes. Immunopharmacology. 1999; 41 31-44
- 35 Saripalli Y V, Gaspari A A. Focus on: biologicals that affect therapeutic agents in dermatology. J Drugs Dermatol. 2005; 4 233-245
- 36 Andreakos E, Foxwell B, Feldmann M. Is targeting Toll-like receptors and their signaling pathway a useful therapeutic approach to modulating cytokine-driven inflammation?. Immunol Rev. 2004; 202 250-265
- 37 Powrie F, Leach M W, Mauze S et al. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 SCID mice. Int Immunol. 1993; 5 1461-1471
- 38 Kirdaite G, Lange N, Busso N et al. Protoporphyrin IX photodynamic therapy for synovitis. Arthritis Rheum. 2002; 46 1371-1378
- 39 Fukuda H, Casas A, Batlle A. Aminolaevulinic acid: from its unique biological function to its star role in photodynamic therapy. Int J Biochem Cell Biol. 2005; 37 272-276
- 40 Wirtz S, Becker C, Blumberg R et al. Treatment of T cell-dependent experimental colitis in SCID mice by local administration of an adenovirus expressing IL-18 antisense mRNA. J Immunol. 2002; 168 411-420
- 41 Wächtershäuser A, Stein J. Rationale for the luminal provision of butyrate in intestinal diseases. Eur J Nutr. 2000; 39 164-171
- 42 Verdu E F, Bercik B, Cukrowska B et al. Oral administration of antigens from intestinal flora anaerobic bacteria reduces the severity of experimental acute colitis in BALB/c mice. Clin Exp Immunol. 2000; 120 46-50
- 43 Vermes I, Haanen C, Steffens-Nakken H et al. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J Immunol Methods. 1995; 184 39-51
- 44 D’Haens G, Van Deventer S, Van Hogezand R et al. Endoscopic and histological healing with infliximab anti-tumour necrosis factor antibodies in Crohn’s Disease. A European multicenter trial. Gastroenterology. 1999; 116 1029-1034
- 45 Fossiez F, Banchereau J, Murray R et al. Interleukin-17. Int Rev Immunol. 1998; 16 541-551
- 46 Fujino S, Andoh A, Bamba S et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut. 2003; 52 65-70
- 47 Langrish C L, Chen Y, Blumenschein W M et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005; 201 233-240
- 48 Becker C, Dornhoff H, Neufert C et al. Cutting edge: Il-23 cross-regulates IL-12 production in T cell-dependent experimental colitis. J Immunol. 2006; 177 2760-2764
- 49 Hunt D W, Chan A H. Immunological aspects of photodynamic therapy. Photodynamic News. 1998; 1 2-4
- 50 Yusuf N, Katiyar S K, Elmets C A. The immunosuppressive effects of phthalocyanine photodynamic therapy in mice are mediated by CD4+ and CD8+ T cells and can be adoptively transferred to naïve recipients. Photochem Photobiol. 2008; 84 366-370
- 51 Hryhorenko E A, Rittenhouse-Diakun K, Harvey N S et al. Characterization of endogenous protoporphyrin IX induced by delta-aminolevulinic acid in resting and activated peripheral blood lymphocytes by four-color flow cytometry. Photochem Photobiol. 1998; 67 565-572
- 52 Granville D J, Carthy C M, Jiang H et al. Nuclear-factor-kappa B activation by the photochemotherapeutic agent verteporfin. Blood. 2000; 95 256-262
- 53 Kessel D, Luo Y. Photodynamic therapy: a mitochondrial inducer of apoptosis. Cell Death Differ. 1999; 6 28-35
- 54 Granville D J, Jiang H, An M T et al. Bcl-2 overexpression blocks caspase activation and downstream apoptotic events instigated by photodynamic therapy. Br J Cancer. 1999; 79 95-100
- 55 Itoh J, de la Motte C, Strong S A et al. Decreased Bax expression by mucosal T cells favors resistance to apoptosis in Crohn’s disease (CD). Gut. 2001; 49 35-41
- 56 Jiang H, Granville D J, McManus B M et al. Selective depletion of a thymocyte subset in vitro with an immunomodulatory photosensitizer. Clin Immunol. 1999; 91 178-187
- 57 Lugering A, Lebiedz P, Koch S et al. Apoptosis as a therapeutic tool in IBD?. Ann NY Acad Sci. 2006; 1072 62-77
- 58 Ina K, Itoh J, Fukushima K et al. Resistance of Crohn’s disease T-cells to multiple apoptotic stimuli is associated with a Bcl-2/Bax mucosal imbalance. J Immunol. 1999; 163 1081-1090
- 59 Hryhorenko E A, Oseroff A R, Morgan J et al. Antigen specific and nonspecific modulation of the immune response by aminolevulinic acid based photodynamic therapy. Immunopharmacology. 1998; 40 231-240
- 60 Wong T W, Tracy E, Oseroff A R et al. Photodynamic therapy mediates immediate loss of cellular responsiveness to cytokines and growth factors. Cancer Res. 2003; 63 3812-3818
- 61 King D E, Jiang H, Simkin G O et al. Photodynamic alteration on the surface receptor expression pattern of murine splenic dendritic cells. Scand J Immunol. 1999; 49 184-192
- 62 Panjehpour M, Overholt B F, Phan M N et al. Optimization of light dosimetry for photodynamic therapy of Barrett’s esophagus: efficacy vs. incidence of stricture after treatment. Gastrointestinal Endosc. 2005; 61 13-18
- 63 Perry Y, Epperly M W, Fernando H C et al. Photodynamic therapy induced esophageal stricture – an animal model: from mouse to pig. J Surg Res. 2005; 123 67-74
- 64 Mackenzie G D, Jamieson N F, Novelli M R et al. How light dosimetry influences the efficacy of photodynamic therapy with 5-aminolaevulinic acid for ablation of high-grade dysplasia in Barrett’s esophagus. Lasers Med Sci. 2008; 23 203-210
M.-A. OrtnerMD
Department of Gastroenterology, DMLL
University Hospital “Inselspital” Bern
Murtenstrasse
CH-3010 Bern
Germany
Fax: +41-31-6329765
Email: ma.ortner@bluewin.ch