A deeper look into type 1 diabetes - imaging immune responses during onset of disease

Frontiers in Immunology

Volumn 7, Issue AUG, 2016, Pages

  Christoffersson, Gustaf ^a   von Herrath, Matthias G ^a,b  

^a LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY   (United States)

^b NOVO NORDISK INC   (United States)

Author keywords

Autoimmunity; Confocal; Imaging; Intravital imaging; Microscopy; Type 1 diabetes

Indexed keywords

BIOLUMINESCENCE; COMPUTER ASSISTED TOMOGRAPHY; CYTOTOXIC T LYMPHOCYTE; FLOW CYTOMETRY; FLUORESCENCE IMAGING; HUMAN; IMMUNE RESPONSE; INSULIN DEPENDENT DIABETES MELLITUS; MICROSCOPY; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; POSITRON EMISSION TOMOGRAPHY; REVIEW; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY;

EID: 84989323356     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2016.00313     Document Type: Review

References (95)

1. McCaffrey A, Kay MA, Contag CH. Advancing molecular therapies through in vivo bioluminescent imaging. Mol Imaging (2003) 2(2):75-86. doi:10.1162/153535003322331966
2. Eich T, Eriksson O, Sundin A, Estrada S, Brandhorst D, Brandhorst H, et al. Positron emission tomography: a real-time tool to quantify early islet engraftment in a preclinical large animal model. Transplantation (2007) 84(7):893-8. doi:10.1097/01.tp.0000284730.86567.9f
3. Willekens SM, van der Kroon I, Joosten L, Frielink C, Boerman OC, van den Broek SA, et al. SPECT of transplanted islets of Langerhans by dopamine 2 receptor targeting in a rat model. Mol Pharm (2016) 13(1):85-91. doi:10.1021/acs.molpharmaceut.5b00518
4. Ahrens ET, Bulte JW. Tracking immune cells in vivo using magnetic resonance imaging. Nat Rev Immunol (2013) 13(10):755-63. doi:10.1038/nri3531
5. Park SY, Bell GI. Noninvasive monitoring of changes in pancreatic beta-cell mass by bioluminescent imaging in MIP-luc transgenic mice. Horm Metab Res (2009) 41(1):1-4. doi:10.1055/s-0028-1087209
6. Patel M, Gleason A, O'Malley S, Connolly B, Suresch D, Virostko J, et al. Non-invasive bioluminescence imaging of beta-cell function in obese-hyperglycemic [ob/ob] mice. PLoS One (2014) 9(9):e106693. doi:10.1371/journal.pone.0106693
7. Molnar C, Essand M, Wennberg L, Berne C, Larsson E, Tufveson G, et al. Islet engraftment and revascularization in clinical and experimental transplantation. Cell Transplant (2013) 22(2):243-51. doi:10.3727/096368912X640637
8. Behnam Azad B, Lisok A, Chatterjee S, Poirier JT, Pullambhatla M, Luker GD, et al. Targeted imaging of the atypical chemokine receptor 3 (ACKR3/CXCR7) in human cancer xenografts. J Nucl Med (2016) 57(6):981-8. doi:10.2967/jnumed.115.167932
9. Jursenaite J, Girkontaite I, Mauricas M, Eidukevicius R, Siaurys A, Characiejus D. Bioluminescence imaging of adoptively transferred lymphocytes during allogeneic tumor rejection. Anticancer Res (2015) 35(12):6573-6
10. Lee HW, Yoon SY, Singh TD, Choi YJ, Lee HJ, Park JY, et al. Tracking of dendritic cell migration into lymph nodes using molecular imaging with sodium iodide symporter and enhanced firefly luciferase genes. Sci Rep (2015) 5:9865. doi:10.1038/srep09865
11. Medarova Z, Castillo G, Dai G, Bolotin E, Bogdanov A, Moore A. Noninvasive magnetic resonance imaging of microvascular changes in type 1 diabetes. Diabetes (2007) 56(11):2677-82. doi:10.2337/db07-0822
12. Turvey SE, Swart E, Denis MC, Mahmood U, Benoist C, Weissleder R, et al. Noninvasive imaging of pancreatic inflammation and its reversal in type 1 diabetes. J Clin Invest (2005) 115(9):2454-61. doi:10.1172/JCI25048
13. Gaglia JL, Guimaraes AR, Harisinghani M, Turvey SE, Jackson R, Benoist C, et al. Noninvasive imaging of pancreatic islet inflammation in type 1A diabetes patients. J Clin Invest (2011) 121(1):442-5. doi:10.1172/JCI44339
14. Kriz J, Jirak D, Girman P, Berkova Z, Zacharovova K, Honsova E, et al. Magnetic resonance imaging of pancreatic islets in tolerance and rejection. Transplantation (2005) 80(11):1596-603. doi:10.1097/01.tp.0000183959.73681.b9
15. Christoffersson G, Henriksnas J, Johansson L, Rolny C, Ahlstrom H, Caballero-Corbalan J, et al. Clinical and experimental pancreatic islet transplantation to striated muscle: establishment of a vascular system similar to that in native islets. Diabetes (2010) 59(10):2569-78. doi:10.2337/db10-0205
16. Garnuszek P, Licinska I, Fiedor P, Mazurek AP. The synthesis, radioiodination and preliminary biological study of the new carboxylic derivatives of dithizone. Appl Radiat Isot (1998) 49(12):1563-71. doi:10.1016/S0969-8043(98)00014-1
17. Schneider S, Ueberberg S, Korobeynikov A, Schechinger W, Schwanstecher C, Schwanstecher M, et al. Synthesis and evaluation of a glibenclamide glucose-conjugate: a potential new lead compound for substituted glibenclamide derivatives as islet imaging agents. Regul Pept (2007) 139(1-3):122-7. doi:10.1016/j.regpep.2006.11.004
18. Eriksson O, Jahan M, Johnstrom P, Korsgren O, Sundin A, Halldin C, et al. In vivo and in vitro characterization of [18F]-FE-(+)-DTBZ as a tracer for beta-cell mass. Nucl Med Biol (2010) 37(3):357-63. doi:10.1016/j.nucmedbio.2009.12.004
19. Pattou F, Kerr-Conte J, Wild D. GLP-1-receptor scanning for imaging of human beta cells transplanted in muscle. N Engl J Med (2010) 363(13):1289-90. doi:10.1056/NEJMc1004547
20. Wild D, Behe M, Wicki A, Storch D, Waser B, Gotthardt M, et al. [Lys40(Ahx-DTPA-111In)NH2]exendin-4, a very promising ligand for glucagon-like peptide-1 (GLP-1) receptor targeting. J Nucl Med (2006) 47(12):2025-33
21. Sweet IR, Cook DL, Lernmark A, Greenbaum CJ, Wallen AR, Marcum ES, et al. Systematic screening of potential beta-cell imaging agents. Biochem Biophys Res Commun (2004) 314(4):976-83. doi:10.1016/j.bbrc.2003.12.182
22. Roca M, de Vries EF, Jamar F, Israel O, Signore A. Guidelines for the labelling of leucocytes with (111)In-oxine. Inflammation/Infection Taskgroup of the European Association of Nuclear Medicine. Eur J Nucl Med Mol Imaging (2010) 37(4):835-41. doi:10.1007/s00259-010-1393-5
23. Peters AM, Saverymuttu SH, Reavy HJ, Danpure HJ, Osman S, Lavender JP. Imaging of inflammation with indium-111 tropolonate labeled leukocytes. J Nucl Med (1983) 24(1):39-44
24. de Vries EF, Roca M, Jamar F, Israel O, Signore A. Guidelines for the labelling of leucocytes with (99m)Tc-HMPAO. Inflammation/Infection Taskgroup of the European Association of Nuclear Medicine. Eur J Nucl Med Mol Imaging (2010) 37(4):842-8. doi:10.1007/s00259-010-1394-4
25. Gallina DL, Pelletier D, Doherty P, Koevary SB, Williams RM, Like AA, et al. 111Indium-labelled lymphocytes do not image or label the pancreas of the BB/W rat. Diabetologia (1985) 28(3):143-7
26. Signore A, Parman A, Pozzilli P, Andreani D, Beverley PC. Detection of activated lymphocytes in endocrine pancreas of BB/W rats by injection of 123I-interleukin-2: an early sign of type 1 diabetes. Lancet (1987) 2(8558):537-40. doi:10.1016/S0140-6736(87)92925-4
27. Barone R, Procaccini E, Chianelli M, Annovazzi A, Fiore V, Hawa M, et al. Prognostic relevance of pancreatic uptake of technetium-99m labelled human polyclonal immunoglobulins in patients with type 1 diabetes. Eur J Nucl Med (1998) 25(5):503-8. doi:10.1007/s002590050250
28. Malviya G, D'Alessandria C, Bonanno E, Vexler V, Massari R, Trotta C, et al. Radiolabeled humanized anti-CD3 monoclonal antibody visilizumab for imaging human T-lymphocytes. J Nucl Med (2009) 50(10):1683-91. doi:10.2967/jnumed.108.059485
29. Minsky M. Memoir on inventing the confocal microscope. Scanning (1988) 10:128-38. doi:10.1002/sca.4950100403
30. Denk W, Strickler JH, Webb WW. Two-photon laser scanning fluorescence microscopy. Science (1990) 248(4951):73-6. doi:10.1126/science.2321027
31. Campagnola PJ, Loew LM. Second-harmonic imaging microscopy for visualizing biomolecular arrays in cells, tissues and organisms. Nat Biotechnol (2003) 21(11):1356-60. doi:10.1038/nbt894
32. Debarre D, Supatto W, Pena AM, Fabre A, Tordjmann T, Combettes L, et al. Imaging lipid bodies in cells and tissues using third-harmonic generation microscopy. Nat Methods (2006) 3(1):47-53. doi:10.1038/nmeth813
33. Muller M, Zumbusch A. Coherent anti-stokes Raman scattering microscopy. Chemphyschem (2007) 8(15):2156-70. doi:10.1002/cphc.200700202
34. Fu Y, Huff TB, Wang HW, Wang H, Cheng JX. Ex vivo and in vivo imaging of myelin fibers in mouse brain by coherent anti-stokes Raman scattering microscopy. Opt Express (2008) 16(24):19396-409. doi:10.1364/OE.16.019396
35. Le TT, Yue S, Cheng JX. Shedding new light on lipid biology with coherent anti-stokes Raman scattering microscopy. J Lipid Res (2010) 51(11):3091-102. doi:10.1194/jlr.R008730
36. Bakker GJ, Andresen V, Hoffman RM, Friedl P. Fluorescence lifetime microscopy of tumor cell invasion, drug delivery, and cytotoxicity. Methods Enzymol (2012) 504:109-25. doi:10.1016/B978-0-12-391857-4.00005-7
37. Levitt JA, Matthews DR, Ameer-Beg SM, Suhling K. Fluorescence lifetime and polarization-resolved imaging in cell biology. Curr Opin Biotechnol (2009) 20(1):28-36. doi:10.1016/j.copbio.2009.01.004
38. Provenzano PP, Eliceiri KW, Keely PJ. Multiphoton microscopy and fluorescence lifetime imaging microscopy (FLIM) to monitor metastasis and the tumor microenvironment. Clin Exp Metastasis (2009) 26(4):357-70. doi:10.1007/s10585-008-9204-0
39. Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW, Sher A, et al. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol (2000) 20(11):4106-14. doi:10.1128/MCB.20.11.4106-4114.2000
40. Da Silva N, Cortez-Retamozo V, Reinecker HC, Wildgruber M, Hill E, Brown D, et al. A dense network of dendritic cells populates the murine epididymis. Reproduction (2011) 141(5):653-63. doi:10.1530/REP-10-0493
41. Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med (2007) 204(12):3037-47. doi:10.1084/jem.20070885
42. Auffray C, Fogg D, Garfa M, Elain G, Join-Lambert O, Kayal S, et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science (2007) 317(5838):666-70. doi:10.1126/science.1142883
43. Schramm R, Schafers HJ, Harder Y, Schmits R, Thorlacius H, Menger MD. The cervical lymph node preparation: a novel approach to study lymphocyte homing by intravital microscopy. Inflamm Res (2006) 55(4):160-7. doi:10.1007/s00011-006-0066-0
44. Lammermann T, Afonso PV, Angermann BR, Wang JM, Kastenmuller W, Parent CA, et al. Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature (2013) 498(7454):371-5. doi:10.1038/nature12175
45. Dzhagalov IL, Melichar HJ, Ross JO, Herzmark P, Robey EA. Two-photon imaging of the immune system. Curr Protoc Cytom (2012) Chapter 12:Unit12.26. doi:10.1002/0471142956.cy1226s60
46. Phillipson M, Heit B, Colarusso P, Liu L, Ballantyne CM, Kubes P. Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade. J Exp Med (2006) 203(12):2569-75. doi:10.1084/jem.20060925
47. Wang J, Kubes P. A reservoir of mature cavity macrophages that can rapidly invade visceral organs to affect tissue repair. Cell (2016) 165(3):668-78. doi:10.1016/j.cell.2016.03.009
48. Victora GD, Schwickert TA, Fooksman DR, Kamphorst AO, Meyer-Hermann M, Dustin ML, et al. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell (2010) 143(4):592-605. doi:10.1016/j.cell.2010.10.032
49. McDonald B, Pittman K, Menezes GB, Hirota SA, Slaba I, Waterhouse CC, et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science (2010) 330(6002):362-6. doi:10.1126/science.1195491
50. Hellerstrom C, Hellman B. The blood circulation in the islets of Langerhans visualized by the fluorescent dye vasoflavine. Studies in normal and obese-hyperglycemic mice. Acta Soc Med Ups (1961) 66:88-94
51. McCuskey RS, Chapman TM. Microscopy of the living pancreas in situ. Am J Anat (1969) 126(4):395-407. doi:10.1002/aja.1001260402
52. Rooth P, Grankvist K, Taljedal IB. In vivo fluorescence microscopy of blood flow in mouse pancreatic islets: adrenergic effects in lean and obese-hyperglycemic mice. Microvasc Res (1985) 30(2):176-84. doi:10.1016/0026-2862(85)90048-2
53. Martinic MM, von Herrath MG. Real-time imaging of the pancreas during development of diabetes. Immunol Rev (2008) 221:200-13. doi:10.1111/j.1600-065X.2008.00581.x
54. Coppieters K, Martinic MM, Kiosses WB, Amirian N, von Herrath M. A novel technique for the in vivo imaging of autoimmune diabetes development in the pancreas by two-photon microscopy. PLoS One (2010) 5(12):e15732. doi:10.1371/journal.pone.0015732
55. Lindsay RS, Corbin K, Mahne A, Levitt BE, Gebert MJ, Wigton EJ, et al. Antigen recognition in the islets changes with progression of autoimmune islet infiltration. J Immunol (2015) 194(2):522-30. doi:10.4049/jimmunol.1400626
56. Menger MD, Jaeger S, Walter P, Feifel G, Hammersen F, Messmer K. Angiogenesis and hemodynamics of microvasculature of transplanted islets of Langerhans. Diabetes (1989) 38(Suppl 1):199-201. doi:10.2337/diab.38.1.S199
57. Speier S, Nyqvist D, Cabrera O, Yu J, Molano RD, Pileggi A, et al. Noninvasive in vivo imaging of pancreatic islet cell biology. Nat Med (2008) 14(5):574-8. doi:10.1038/nm1701
58. Bertera S, Geng X, Tawadrous Z, Bottino R, Balamurugan AN, Rudert WA, et al. Body window-enabled in vivo multicolor imaging of transplanted mouse islets expressing an insulin-timer fusion protein. Biotechniques (2003) 35(4):718-22
59. Espes D, Lau J, Quach M, Ullsten S, Christoffersson G, Carlsson PO. Rapid restoration of vascularity and oxygenation in mouse and human islets transplanted to omentum may contribute to their superior function compared to intraportally transplanted islets. Am J Transplant (2016). doi:10.1111/ajt.13927
60. Friedman RS, Lindsay RS, Lilly JK, Nguyen V, Sorensen CM, Jacobelli J, et al. An evolving autoimmune microenvironment regulates the quality of effector T cell restimulation and function. Proc Natl Acad Sci U S A (2014) 111(25):9223-8. doi:10.1073/pnas.1322193111
61. Marciniak A, Selck C, Friedrich B, Speier S. Mouse pancreas tissue slice culture facilitates long-term studies of exocrine and endocrine cell physiology in situ. PLoS One (2013) 8(11):e78706. doi:10.1371/journal.pone.0078706
62. Rappaport AM, Kawamura T, Davidson JK, Lin BJ, Oira S, Zeigler M, et al. Effects of hormones and of blood flow on insulin output of isolated pancreas in situ. Am J Physiol (1971) 221(1):343-8
63. Meyer HH, Vetterlein F, Schmidt G, Hasselblatt A. Measurement of blood flow in pancreatic islets of the rat: effect of isoproterenol and norepinephrine. Am J Physiol (1982) 242(5):E298-304
64. Nyman LR, Ford E, Powers AC, Piston DW. Glucose-dependent blood flow dynamics in murine pancreatic islets in vivo. Am J Physiol Endocrinol Metab (2010) 298(4):E807-14. doi:10.1152/ajpendo.00715.2009
65. Coppieters K, Amirian N, von Herrath M. Intravital imaging of CTLs killing islet cells in diabetic mice. J Clin Invest (2012) 122(1):119-31. doi:10.1172/JCI59285
66. Looney MR, Thornton EE, Sen D, Lamm WJ, Glenny RW, Krummel MF. Stabilized imaging of immune surveillance in the mouse lung. Nat Methods (2011) 8(1):91-6. doi:10.1038/nmeth.1543
67. Marciniak A, Cohrs CM, Tsata V, Chouinard JA, Selck C, Stertmann J, et al. Using pancreas tissue slices for in situ studies of islet of Langerhans and acinar cell biology. Nat Protoc (2014) 9(12):2809-22. doi:10.1038/nprot.2014.195
68. Ritsma L, Steller EJ, Beerling E, Loomans CJ, Zomer A, Gerlach C, et al. Intravital microscopy through an abdominal imaging window reveals a pre-micrometastasis stage during liver metastasis. Sci Transl Med (2012) 4(158):158ra45. doi:10.1126/scitranslmed.3004394
69. Bochner F, Fellus-Alyagor L, Kalchenko V, Shinar S, Neeman M. A novel intravital imaging window for longitudinal microscopy of the mouse ovary. Sci Rep (2015) 5:12446. doi:10.1038/srep12446
70. Kedrin D, Gligorijevic B, Wyckoff J, Verkhusha VV, Condeelis J, Segall JE, et al. Intravital imaging of metastatic behavior through a mammary imaging window. Nat Methods (2008) 5(12):1019-21. doi:10.1038/nmeth.1269
71. Gerner MY, Kastenmuller W, Ifrim I, Kabat J, Germain RN. Histo-cytometry: a method for highly multiplex quantitative tissue imaging analysis applied to dendritic cell subset microanatomy in lymph nodes. Immunity (2012) 37(2):364-76. doi:10.1016/j.immuni.2012.07.011
72. Menger MD, Vajkoczy P, Beger C, Messmer K. Orientation of microvascular blood flow in pancreatic islet isografts. J Clin Invest (1994) 93(5):2280-5. doi:10.1172/JCI117228
73. Christoffersson G, Vagesjo E, Vandooren J, Liden M, Massena S, Reinert RB, et al. VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue. Blood (2012) 120(23):4653-62. doi:10.1182/blood-2012-04-421040
74. Coupland RE. Growth of pancreatic islet tissue in the anterior chamber of the eye. Nature (1957) 179(4549):51-2. doi:10.1038/179051b0
75. Speier S, Nyqvist D, Kohler M, Caicedo A, Leibiger IB, Berggren PO. Noninvasive high-resolution in vivo imaging of cell biology in the anterior chamber of the mouse eye. Nat Protoc (2008) 3(8):1278-86. doi:10.1038/nprot.2008.118
76. Faleo G, Berggren PO, Pileggi A. Intravital imaging of cytotoxic T lymphocytes. Methods Mol Biol (2014) 1186:121-9. doi:10.1007/978-1-4939-1158-5_9
77. Schmidt-Christensen A, Hansen L, Ilegems E, Fransen-Pettersson N, Dahl U, Gupta S, et al. Imaging dynamics of CD11c(+) cells and Foxp3(+) cells in progressive autoimmune insulitis in the NOD mouse model of type 1 diabetes. Diabetologia (2013) 56(12):2669-78. doi:10.1007/s00125-013-3024-8
78. Lammermann T, Bader BL, Monkley SJ, Worbs T, Wedlich-Soldner R, Hirsch K, et al. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature (2008) 453(7191):51-5. doi:10.1038/nature06887
79. Yin N, Zhang N, Lal G, Xu J, Yan M, Ding Y, et al. Lymphangiogenesis is required for pancreatic islet inflammation and diabetes. PLoS One (2011) 6(11):e28023. doi:10.1371/journal.pone.0028023
80. Calderon B, Carrero JA, Ferris ST, Sojka DK, Moore L, Epelman S, et al. The pancreas anatomy conditions the origin and properties of resident macrophages. J Exp Med (2015) 212(10):1497-512. doi:10.1084/jem.20150496
81. Ohashi PS, Oehen S, Buerki K, Pircher H, Ohashi CT, Odermatt B, et al. Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice. Cell (1991) 65(2):305-17. doi:10.1016/0092-8674(91)90164-T
82. Korpos E, Kadri N, Kappelhoff R, Wegner J, Overall CM, Weber E, et al. The peri-islet basement membrane, a barrier to infiltrating leukocytes in type 1 diabetes in mouse and human. Diabetes (2013) 62(2):531-42. doi:10.2337/db12-0432
83. Van Belle TL, Taylor P, von Herrath MG. Mouse models for type 1 diabetes. Drug Discov Today Dis Models (2009) 6(2):41-5. doi:10.1016/j.ddmod.2009.03.008
84. Oldstone MB, Edelmann KH, McGavern DB, Cruite JT, Welch MJ. Molecular anatomy and number of antigen specific CD8 T cells required to cause type 1 diabetes. PLoS Pathog (2012) 8(11):e1003044. doi:10.1371/journal.ppat.1003044
85. Coppieters KT, Dotta F, Amirian N, Campbell PD, Kay TW, Atkinson MA, et al. Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J Exp Med (2012) 209(1):51-60. doi:10.1084/jem.20111187
86. Magnuson AM, Thurber GM, Kohler RH, Weissleder R, Mathis D, Benoist C. Population dynamics of islet-infiltrating cells in autoimmune diabetes. Proc Natl Acad Sci U S A (2015) 112(5):1511-6. doi:10.1073/pnas.1423769112
87. Tomura M, Yoshida N, Tanaka J, Karasawa S, Miwa Y, Miyawaki A, et al. Monitoring cellular movement in vivo with photoconvertible fluorescence protein "Kaede" transgenic mice. Proc Natl Acad Sci U S A (2008) 105(31):10871-6. doi:10.1073/pnas.0802278105
88. Perdigoto AL, Chatenoud L, Bluestone JA, Herold KC. Inducing and administering Tregs to treat human disease. Front Immunol (2015) 6:654. doi:10.3389/fimmu.2015.00654
89. Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med (2015) 7(315):315ra189. doi:10.1126/scitranslmed.aad4134
90. Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol (2006) 7(1):83-92. doi:10.1038/ni1289
91. Miska J, Abdulreda MH, Devarajan P, Lui JB, Suzuki J, Pileggi A, et al. Real-time immune cell interactions in target tissue during autoimmune-induced damage and graft tolerance. J Exp Med (2014) 211(3):441-56. doi:10.1084/jem.20130785
92. Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, Becker DJ, Gitelman SE, Goland R, et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med (2009) 361(22):2143-52. doi:10.1056/NEJMoa0904452
93. Diana J, Simoni Y, Furio L, Beaudoin L, Agerberth B, Barrat F, et al. Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes. Nat Med (2013) 19(1):65-73. doi:10.1038/nm.3042
94. Fisher DT, Muhitch JB, Kim M, Doyen KC, Bogner PN, Evans SS, et al. Intraoperative intravital microscopy permits the study of human tumour vessels. Nat Commun (2016) 7:10684. doi:10.1038/ncomms10684
95. Napoleon B, Lemaistre AI, Pujol B, Caillol F, Lucidarme D, Bourdariat R, et al. A novel approach to the diagnosis of pancreatic serous cystadenoma: needle-based confocal laser endomicroscopy. Endoscopy (2015) 47(1):26-32. doi:10.1055/s-0034-1390693