Immunological Considerations for Retinal Stem Cell Therapy

  • Joshua Kramer
  • Kathleen R. Chirco
  • Deepak A. LambaEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1186)


There is an increasing effort toward generating replacement cells for neuronal application due to the nonregenerative nature of these tissues. While much progress has been made toward developing methodologies to generate these cells, there have been limited improvements in functional restoration. Some of these are linked to the degenerative and often nonreceptive microenvironment that the new cells need to integrate into. In this chapter, we will focus on the status and role of the immune microenvironment of the retina during homeostasis and disease states. We will review changes in both innate and adaptive immunity as well as the role of immune rejection in stem cell replacement therapies. The chapter will end with a discussion of immune-modulatory strategies that have helped to ameliorate these effects and could potentially improve functional outcome for cell replacement therapies for the eye.


Immune modulation Cell replacement Microglia Macrophages Muller glia Complement system Immune rejection Inflammasome 


  1. 1.
    Davis RJ, Blenkinsop TA, Campbell M, Borden SM, Charniga CJ, Lederman PL, Frye AM, Aguilar V, Zhao C, Naimark M et al (2016) Human RPE stem cell-derived RPE preserves photoreceptors in the Royal College of Surgeons rat: method for quantifying the area of photoreceptor sparing. J Ocul Pharmacol Ther 32:304–309CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Khristov V, Maminishkis A, Amaral J, Rising A, Bharti K, Miller S (2018) Validation of iPS cell-derived RPE tissue in animal models. Adv Exp Med Biol 1074:633–640CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Lamba DA, Karl MO, Ware CB, Reh TA (2006) Efficient generation of retinal progenitor cells from human embryonic stem cells. Proc Natl Acad Sci U S A 103:12769–12774CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Lamba DA, Gust J, Reh TA (2009) Transplantation of human embryonic stem cell-derived photoreceptors restores some visual function in Crx-deficient mice. Cell Stem Cell 4:73–79CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    McGill TJ, Bohana-Kashtan O, Stoddard JW, Andrews MD, Pandit N, Rosenberg-Belmaker LR, Wiser O, Matzrafi L, Banin E, Reubinoff B et al (2017) Long-term efficacy of GMP grade xeno-free hESC-derived RPE cells following transplantation. Transl Vis Sci Technol 6:17CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Meyer JS, Howden SE, Wallace KA, Verhoeven AD, Wright LS, Capowski EE, Pinilla I, Martin JM, Tian S, Stewart R et al (2011) Optic vesicle-like structures derived from human pluripotent stem cells facilitate a customized approach to retinal disease treatment. Stem Cells 29:1206–1218CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Wu S, Chang K-C, Nahmou M, Goldberg JL (2018) Induced pluripotent stem cells promote retinal ganglion cell survival after transplant. Invest Ophthalmol Vis Sci 59:1571–1576CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Collins KH, Herzog W, Reimer RA, Reno CR, Heard BJ, Hart DA (2018) Diet-induced obesity leads to pro-inflammatory alterations to the vitreous humour of the eye in a rat model. Inflamm Res 67:139–146CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Niederkorn JY (2012) Ocular immune privilege and ocular melanoma: parallel universes or immunological plagiarism? Front Immunol 3:148CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Osuský R, Walker SM, Ryan SJ (1996) Vitreous body affects activation and maturation of monocytes into macrophages. Graefes Arch Clin Exp Ophthalmol 234:637–642CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Arroba AI, Campos-Caro A, Aguilar-Diosdado M, Valverde ÁM (2018) IGF-1, inflammation and retinal degeneration: a close network. Front Aging Neurosci 10:203CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Sugita S, Futagami Y, Smith SB, Naggar H, Mochizuki M (2006) Retinal and ciliary body pigment epithelium suppress activation of T lymphocytes via transforming growth factor beta. Exp Eye Res 83:1459–1471CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Sugita S, Horie S, Nakamura O, Futagami Y, Takase H, Keino H, Aburatani H, Katunuma N, Ishidoh K, Yamamoto Y et al (2008) Retinal pigment epithelium-derived CTLA-2alpha induces TGFbeta-producing T regulatory cells. J Immunol 1950(181):7525–7536CrossRefGoogle Scholar
  14. 14.
    Zhou R, Horai R, Silver PB, Mattapallil MJ, Zárate-Bladés CR, Chong WP, Chen J, Rigden RC, Villasmil R, Caspi RR (2012) The living eye “disarms” uncommitted autoreactive T cells by converting them to FoxP3+ regulatory cells following local antigen recognition. J Immunol 1950(188):1742–1750CrossRefGoogle Scholar
  15. 15.
    Forbes SJ, Rosenthal N (2014) Preparing the ground for tissue regeneration: from mechanism to therapy. Nat Med 20:857–869CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hanisch U-K, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394CrossRefGoogle Scholar
  18. 18.
    Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    London A, Cohen M, Schwartz M (2013) Microglia and monocyte-derived macrophages: functionally distinct populations that act in concert in CNS plasticity and repair. Front Cell Neurosci 7:34CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32:593–604CrossRefGoogle Scholar
  21. 21.
    Martinez FO, Helming L, Gordon S (2009) Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 27:451–483CrossRefGoogle Scholar
  22. 22.
    Chen M, Luo C, Zhao J, Devarajan G, Xu H (2019) Immune regulation in the aging retina. Prog Retin Eye Res 69:159–172CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Li L, Eter N, Heiduschka P (2015) The microglia in healthy and diseased retina. Exp Eye Res 136:116–130CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Rathnasamy G, Foulds WS, Ling E-A, Kaur C (2018) Retinal microglia—a key player in healthy and diseased retina. Prog Neurobiol 173:18–40CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Hagemeyer N, Hanft K-M, Akriditou M-A, Unger N, Park ES, Stanley ER, Staszewski O, Dimou L, Prinz M (2017) Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood. Acta Neuropathol (Berl) 134:441–458CrossRefGoogle Scholar
  26. 26.
    Kim S-Y (2015) Retinal phagocytes in age-related macular degeneration. Macrophage 2:e698PubMedPubMedCentralGoogle Scholar
  27. 27.
    Prinz M, Erny D, Hagemeyer N (2017) Ontogeny and homeostasis of CNS myeloid cells. Nat Immunol 18:385–392CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Sedel F, Béchade C, Vyas S, Triller A (2004) Macrophage-derived tumor necrosis factor alpha, an early developmental signal for motoneuron death. J Neurosci 24:2236–2246CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Casano AM, Albert M, Peri F (2016) Developmental apoptosis mediates entry and positioning of microglia in the zebrafish brain. Cell Rep 16:897–906CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Silverman SM, Wong WT (2018) Microglia in the retina: roles in development, maturity, and disease. Annu Rev Vis Sci 4:45–77CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Wang X, Zhao L, Zhang J, Fariss RN, Ma W, Kretschmer F, Wang M, Qian HH, Badea TC, Diamond JS et al (2016) Requirement for microglia for the maintenance of synaptic function and integrity in the mature retina. J Neurosci 36:2827–2842CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Xu J, Wang T, Wu Y, Jin W, Wen Z (2016) Microglia colonization of developing zebrafish midbrain is promoted by apoptotic neuron and lysophosphatidylcholine. Dev Cell 38:214–222CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Arnold T, Betsholtz C (2013) The importance of microglia in the development of the vasculature in the central nervous system. Vasc Cell 5:4CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Frost JL, Schafer DP (2016) Microglia: architects of the developing nervous system. Trends Cell Biol 26:587–597CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Nakanishi M, Niidome T, Matsuda S, Akaike A, Kihara T, Sugimoto H (2007) Microglia-derived interleukin-6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem/progenitor cells. Eur J Neurosci 25:649–658CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Ma W, Zhang Y, Gao C, Fariss RN, Tam J, Wong WT (2017) Monocyte infiltration and proliferation reestablish myeloid cell homeostasis in the mouse retina following retinal pigment epithelial cell injury. Sci Rep 7:8433CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    O’Koren EG, Mathew R, Saban DR (2016) Fate mapping reveals that microglia and recruited monocyte-derived macrophages are definitively distinguishable by phenotype in the retina. Sci Rep 6:20636CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    MacDonald RB, Charlton-Perkins M, Harris WA (2017) Mechanisms of Müller glial cell morphogenesis. Curr Opin Neurobiol 47:31–37CrossRefGoogle Scholar
  39. 39.
    Subirada PV, Paz MC, Ridano ME, Lorenc VE, Vaglienti MV, Barcelona PF, Luna JD, Sánchez MC (2018) A journey into the retina: Müller glia commanding survival and death. Eur J Neurosci 47:1429–1443CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Wang J, O’Sullivan ML, Mukherjee D, Puñal VM, Farsiu S, Kay JN (2017) Anatomy and spatial organization of Müller glia in mouse retina. J Comp Neurol 525:1759–1777CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Wing K, Sakaguchi S (2010) Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol 11:7–13CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Josefowicz SZ, Lu L-F, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Burzyn D, Kuswanto W, Kolodin D, Shadrach JL, Cerletti M, Jang Y, Sefik E, Tan TG, Wagers AJ, Benoist C et al (2013) A special population of regulatory T cells potentiates muscle repair. Cell 155:1282–1295CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Burzyn D, Benoist C, Mathis D (2013) Regulatory T cells in nonlymphoid tissues. Nat Immunol 14:1007–1013CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Holers VM (2014) Complement and its receptors: new insights into human disease. Annu Rev Immunol 32:433–459CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Haynes T, Luz-Madrigal A, Reis ES, Echeverri Ruiz NP, Grajales-Esquivel E, Tzekou A, Tsonis PA, Lambris JD, Del Rio-Tsonis K (2013) Complement anaphylatoxin C3a is a potent inducer of embryonic chick retina regeneration. Nat Commun 4:2312CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Hawksworth OA, Coulthard LG, Woodruff TM (2017) Complement in the fundamental processes of the cell. Mol Immunol 84:17–25CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Mullins RF, Schoo DP, Sohn EH, Flamme-Wiese MJ, Workamelahu G, Johnston RM, Wang K, Tucker BA, Stone EM (2014) The membrane attack complex in aging human choriocapillaris: relationship to macular degeneration and choroidal thinning. Am J Pathol 184:3142–3153CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Karlstetter M, Scholz R, Rutar M, Wong WT, Provis JM, Langmann T (2015) Retinal microglia: just bystander or target for therapy? Prog Retin Eye Res 45:30–57CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Hu R, Kagele DA, Huffaker TB, Runtsch MC, Alexander M, Liu J, Bake E, Su W, Williams MA, Rao DS et al (2014) miR-155 promotes T follicular helper cell accumulation during chronic, low-grade inflammation. Immunity 41:605–619CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Cuenca N, Fernández-Sánchez L, Campello L, Maneu V, De la Villa P, Lax P, Pinilla I (2014) Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases. Prog Retin Eye Res 43:17–75CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Bringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P, Skatchkov SN, Osborne NN, Reichenbach A (2006) Müller cells in the healthy and diseased retina. Prog Retin Eye Res 25:397–424CrossRefGoogle Scholar
  53. 53.
    Martinez FO, Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 6:13CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Yin Y, Henzl MT, Lorber B, Nakazawa T, Thomas TT, Jiang F, Langer R, Benowitz LI (2006) Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells. Nat Neurosci 9:843–852CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Suh H-S, Zhao M-L, Derico L, Choi N, Lee SC (2013) Insulin-like growth factor 1 and 2 (IGF1, IGF2) expression in human microglia: differential regulation by inflammatory mediators. J Neuroinflammation 10:37CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Krause TA, Alex AF, Engel DR, Kurts C, Eter N (2014) VEGF-production by CCR2-dependent macrophages contributes to laser-induced choroidal neovascularization. PLoS One 9:e94313CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Liu J, Copland DA, Horie S, Wu W-K, Chen M, Xu Y, Paul Morgan B, Mack M, Xu H, Nicholson LB et al (2013) Myeloid cells expressing VEGF and arginase-1 following uptake of damaged retinal pigment epithelium suggests potential mechanism that drives the onset of choroidal angiogenesis in mice. PLoS One 8:e72935CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Miron VE, Boyd A, Zhao J-W, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ, Williams A, Franklin RJM et al (2013) M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 16:1211–1218CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122:787–795CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Cherry JD, Olschowka JA, O’Banion MK (2014) Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation 11:98CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Shaw AC, Goldstein DR, Montgomery RR (2013) Age-dependent dysregulation of innate immunity. Nat Rev Immunol 13:875–887CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Madeira MH, Rashid K, Ambrósio AF, Santiago AR, Langmann T (2018) Blockade of microglial adenosine A2A receptor impacts inflammatory mechanisms, reduces ARPE-19 cell dysfunction and prevents photoreceptor loss in vitro. Sci Rep 8:2272CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Song D, Sulewski ME, Wang C, Song J, Bhuyan R, Sterling J, Clark E, Song W-C, Dunaief JL (2017) Complement C5a receptor knockout has diminished light-induced microglia/macrophage retinal migration. Mol Vis 23:210–218PubMedPubMedCentralGoogle Scholar
  64. 64.
    Hippert C, Graca AB, Barber AC, West EL, Smith AJ, Ali RR, Pearson RA (2015) Müller glia activation in response to inherited retinal degeneration is highly varied and disease-specific. PLoS One 10:e0120415CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Crespo D, Asher RA, Lin R, Rhodes KE, Fawcett JW (2007) How does chondroitinase promote functional recovery in the damaged CNS? Exp Neurol 206:159–171CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    McKeon RJ, Schreiber RC, Rudge JS, Silver J (1991) Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. J Neurosci 11:3398–3411CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Xi H, Katschke KJ, Li Y, Truong T, Lee WP, Diehl L, Rangell L, Tao J, Arceo R, Eastham-Anderson J et al (2016) IL-33 amplifies an innate immune response in the degenerating retina. J Exp Med 213:189–207CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Rutar M, Natoli R, Provis JM (2012) Small interfering RNA-mediated suppression of Ccl2 in Müller cells attenuates microglial recruitment and photoreceptor death following retinal degeneration. J Neuroinflammation 9:221PubMedPubMedCentralGoogle Scholar
  69. 69.
    Graca AB, Hippert C, Pearson RA (2018) Müller Glia reactivity and development of gliosis in response to pathological conditions. Adv Exp Med Biol 1074:303–308CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Radtke ND, Aramant RB, Seiler M, Petry HM (1999) Preliminary report: indications of improved visual function after retinal sheet transplantation in retinitis pigmentosa patients. Am J Ophthalmol 128:384–387CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Arroba AI, Alvarez-Lindo N, van Rooijen N, de la Rosa EJ (2014) Microglia-Müller glia crosstalk in the rd10 mouse model of retinitis pigmentosa. Adv Exp Med Biol 801:373–379CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Roche SL, Ruiz-Lopez AM, Moloney JN, Byrne AM, Cotter TG (2018) Microglial-induced Müller cell gliosis is attenuated by progesterone in a mouse model of retinitis pigmentosa. Glia 66:295–310CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Portillo J-AC, Lopez Corcino Y, Miao Y, Tang J, Sheibani N, Kern TS, Dubyak GR, Subauste CS (2017) CD40 in retinal Müller cells induces P2X7-dependent cytokine expression in macrophages/microglia in diabetic mice and development of early experimental diabetic retinopathy. Diabetes 66:483–493CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Samuels IS, Portillo J-AC, Miao Y, Kern TS, Subauste CS (2017) Loss of CD40 attenuates experimental diabetes-induced retinal inflammation but does not protect mice from electroretinogram defects. Vis Neurosci 34:E009CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Wang J, Westenskow PD, Fang M, Friedlander M, Siuzdak G (2016) Quantitative metabolomics of photoreceptor degeneration and the effects of stem cell-derived retinal pigment epithelium transplantation. Philos Trans Math Phys Eng Sci 374:20150376CrossRefGoogle Scholar
  76. 76.
    Kerur N, Hirano Y, Tarallo V, Fowler BJ, Bastos-Carvalho A, Yasuma T, Yasuma R, Kim Y, Hinton DR, Kirschning CJ et al (2013) TLR-independent and P2X7-dependent signaling mediate Alu RNA-induced NLRP3 inflammasome activation in geographic atrophy. Invest Ophthalmol Vis Sci 54:7395–7401CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Nebel C, Aslanidis A, Rashid K, Langmann T (2017) Activated microglia trigger inflammasome activation and lysosomal destabilization in human RPE cells. Biochem Biophys Res Commun 484:681–686CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Doyle SL, Campbell M, Ozaki E, Salomon RG, Mori A, Kenna PF, Farrar GJ, Kiang A-S, Humphries MM, Lavelle EC et al (2012) NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components. Nat Med 18:791–798CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Asgari E, Le Friec G, Yamamoto H, Perucha E, Sacks SS, Köhl J, Cook HT, Kemper C (2013) C3a modulates IL-1β secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation. Blood 122:3473–3481CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Triantafilou K, Hughes TR, Triantafilou M, Morgan BP (2013) The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflammasome activation. J Cell Sci 126:2903–2913CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 9:857–865CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Heid ME, Keyel PA, Kamga C, Shiva S, Watkins SC, Salter RD (2013) Mitochondrial reactive oxygen species induces NLRP3-dependent lysosomal damage and inflammasome activation. J Immunol 191:5230–5238CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Guo H, Callaway JB, Ting JP-Y (2015) Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 21:677–687CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Zeng S, Whitmore SS, Sohn EH, Riker MJ, Wiley LA, Scheetz TE, Stone EM, Tucker BA, Mullins RF (2016) Molecular response of chorioretinal endothelial cells to complement injury: implications for macular degeneration. J Pathol 238:446–456CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    West EL, Pearson RA, Barker SE, Luhmann UFO, Maclaren RE, Barber AC, Duran Y, Smith AJ, Sowden JC, Ali RR (2010) Long-term survival of photoreceptors transplanted into the adult murine neural retina requires immune modulation. Stem Cells 28:1997–2007CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Pearson RA, Gonzalez-Cordero A, West EL, Ribeiro JR, Aghaizu N, Goh D, Sampson RD, Georgiadis A, Waldron PV, Duran Y et al (2016) Donor and host photoreceptors engage in material transfer following transplantation of post-mitotic photoreceptor precursors. Nat Commun 7:13029CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Santos-Ferreira T, Llonch S, Borsch O, Postel K, Haas J, Ader M (2016) Retinal transplantation of photoreceptors results in donor-host cytoplasmic exchange. Nat Commun 7:13028CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Singh MS, Balmer J, Barnard AR, Aslam SA, Moralli D, Green CM, Barnea-Cramer A, Duncan I, MacLaren RE (2016) Transplanted photoreceptor precursors transfer proteins to host photoreceptors by a mechanism of cytoplasmic fusion. Nat Commun 7:13537CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Waldron PV, Di Marco F, Kruczek K, Ribeiro J, Graca AB, Hippert C, Aghaizu ND, Kalargyrou AA, Barber AC, Grimaldi G et al (2018) Transplanted donor- or stem cell-derived cone photoreceptors can both integrate and undergo material transfer in an environment-dependent manner. Stem Cell Rep 10:406–421CrossRefGoogle Scholar
  90. 90.
    Jiang LQ, Jorquera M, Streilein JW, Ishioka M (1995) Unconventional rejection of neural retinal allografts implanted into the immunologically privileged site of the eye. Transplantation 59:1201–1207CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Seiler MJ, Aramant RB, Jones MK, Ferguson DL, Bryda EC, Keirstead HS (2014) A new immunodeficient pigmented retinal degenerate rat strain to study transplantation of human cells without immunosuppression. Graefes Arch Clin Exp Ophthalmol 252:1079–1092CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Zhu J, Cifuentes H, Reynolds J, Lamba DA (2017) Immunosuppression via loss of IL2rgamma enhances long-term functional integration of hESC-derived photoreceptors in the mouse retina. Cell Stem Cell 20:374–384.e5CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Cao X, Shores EW, Hu-Li J, Anver MR, Kelsall BL, Russell SM, Drago J, Noguchi M, Grinberg A, Bloom ET et al (1995) Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity 2:223–238CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Zhu J, Reynolds J, Garcia T, Cifuentes H, Chew S, Zeng X, Lamba DA (2018) Generation of transplantable retinal photoreceptors from a current good manufacturing practice-manufactured human induced pluripotent stem cell line. Stem Cells Transl Med 7:210–219CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Sugita S, Iwasaki Y, Makabe K, Kamao H, Mandai M, Shiina T, Ogasawara K, Hirami Y, Kurimoto Y, Takahashi M (2016) Successful transplantation of retinal pigment epithelial cells from MHC homozygote iPSCs in MHC-matched models. Stem Cell Rep 7:635–648CrossRefGoogle Scholar
  96. 96.
    Sugita S, Makabe K, Fujii S, Iwasaki Y, Kamao H, Shiina T, Ogasawara K, Takahashi M (2017) Detection of retinal pigment epithelium-specific antibody in iPSC-derived retinal pigment epithelium transplantation models. Stem Cell Rep 9:1501–1515CrossRefGoogle Scholar
  97. 97.
    McGill TJ, Stoddard J, Renner LM, Messaoudi I, Bharti K, Mitalipov S, Lauer A, Wilson DJ, Neuringer M (2018) Allogeneic iPSC-derived RPE cell graft failure following transplantation into the subretinal space in nonhuman primates. Invest Ophthalmol Vis Sci 59:1374–1383CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Sohn EH, Jiao C, Kaalberg E, Cranston C, Mullins RF, Stone EM, Tucker BA (2015) Allogenic iPSC-derived RPE cell transplants induce immune response in pigs: a pilot study. Sci Rep 5:11791CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Morinaga C, Daimon T, Fujihara M, Akimaru H, Sakai N, Shibata Y et al (2017) Autologous induced stem-cell-derived retinal cells for macular degeneration. N Engl J Med 376:1038–1046CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Ruiz S, Diep D, Gore A, Panopoulos AD, Montserrat N, Plongthongkum N, Kumar S, Fung H-L, Giorgetti A, Bilic J et al (2012) Identification of a specific reprogramming-associated epigenetic signature in human induced pluripotent stem cells. Proc Natl Acad Sci U S A 109:16196–16201CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Gourraud P-A, Gilson L, Girard M, Peschanski M (2012) The role of human leukocyte antigen matching in the development of multiethnic “haplobank” of induced pluripotent stem cell lines. Stem Cells Dayt Ohio 30:180–186CrossRefGoogle Scholar
  102. 102.
    Turner M, Leslie S, Martin NG, Peschanski M, Rao M, Taylor CJ, Trounson A, Turner D, Yamanaka S, Wilmut I (2013) Toward the development of a global induced pluripotent stem cell library. Cell Stem Cell 13:382–384CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Nakajima F, Tokunaga K, Nakatsuji N (2007) Human leukocyte antigen matching estimations in a hypothetical bank of human embryonic stem cell lines in the Japanese population for use in cell transplantation therapy. Stem Cells Dayt Ohio 25:983–985CrossRefGoogle Scholar
  104. 104.
    Pappas DJ, Gourraud P-A, Gall CL, Laurent J, Trounson A, DeWitt N, Talib S (2015) Proceedings: Human leukocyte antigen haplo-homozygous induced pluripotent stem cell haplobank modeled after the California population: evaluating matching in a multiethnic and admixed population. Stem Cells Transl Med 4:413–418CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Lee S, Huh JY, Turner DM, Lee S, Robinson J, Stein JE, Shim SH, Hong CP, Kang MS, Nakagawa M et al (2018) Repurposing the cord blood bank for haplobanking of HLA-homozygous iPSCs and their usefulness to multiple populations. Stem Cells 36:1552–1566CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Riolobos L, Hirata RK, Turtle CJ, Wang P-R, Gornalusse GG, Zavajlevski M, Riddell SR, Russell DW (2013) HLA engineering of human pluripotent stem cells. Mol Ther 21:1232–1241CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Gornalusse GG, Hirata RK, Funk SE, Riolobos L, Lopes VS, Manske G, Prunkard D, Colunga AG, Hanafi L-A, Clegg DO et al (2017) HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells. Nat Biotechnol 35:765–772CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Sugita S, Makabe K, Iwasaki Y, Fujii S, Takahashi M (2018) Natural killer cell inhibition by HLA-E molecules on induced pluripotent stem cell-derived retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 59:1719–1731CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    de Ataide EC, Perales SR, Bortoto JB, Peres MAO, Filho FC, Stucchi RSB, Udo E, Boin IFSF (2017) Immunomodulation, acute renal failure, and complications of basiliximab use after liver transplantation: analysis of 114 patients and literature review. Transplant Proc 49:852–857CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Kittipibul V, Tantrachoti P, Ongcharit P, Ariyachaipanich A, Siwamogsatham S, Sritangsirikul S, Thammanatsakul K, Puwanant S (2017) Low-dose basiliximab induction therapy in heart transplantation. Clin Transplant 31.
  111. 111.
    Zhang G-Q, Zhang C-S, Sun N, Lv W, Chen B-M, Zhang J-L (2017) Basiliximab application on liver recipients: a meta-analysis of randomized controlled trials. Hepatobiliary Pancreat Dis Int 16:139–146CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Franchimont D (2004) Overview of the actions of glucocorticoids on the immune response: a good model to characterize new pathways of immunosuppression for new treatment strategies. Ann N Y Acad Sci 1024:124–137CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Pan Q, Xu Q, Boylan NJ, Lamb NW, Emmert DG, Yang J-C, Tang L, Heflin T, Alwadani S, Eberhart CG et al (2015) Corticosteroid-loaded biodegradable nanoparticles for prevention of corneal allograft rejection in rats. J Control Release 201:32–40CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Young AL, Rao SK, Cheng LL, Wong AKK, Leung ATS, Lam DSC (2002) Combined intravenous pulse methylprednisolone and oral cyclosporine A in the treatment of corneal graft rejection: 5-year experience. Eye (Lond) 16:304–308CrossRefGoogle Scholar
  115. 115.
    Sen HN, Abreu FM, Louis TA, Sugar EA, Altaweel MM, Elner SG, Holbrook JT, Jabs DA, Kim RY, Kempen JH (2016) Cataract surgery outcomes in uveitis: the multicenter uveitis steroid treatment trial. Ophthalmology 123:183–190CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Neves J, Zhu J, Sousa-Victor P, Konjikusic M, Riley R, Chew S, Qi Y, Jasper H, Lamba DA (2016) Immune modulation by MANF promotes tissue repair and regenerative success in the retina. Science 353:aaf3646CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Tonkin J, Temmerman L, Sampson RD, Gallego-Colon E, Barberi L, Bilbao D, Schneider MD, Musarò A, Rosenthal N (2015) Monocyte/macrophage-derived IGF-1 orchestrates murine skeletal muscle regeneration and modulates autocrine polarization. Mol Ther 23:1189–1200CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Prencipe G, Minnone G, Strippoli R, Pasquale LD, Petrini S, Caiello I, Manni L, Benedetti FD, Bracci-Laudiero L (2014) Nerve growth factor downregulates inflammatory response in human monocytes through TrkA. J Immunol 192:3345–3354CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Calabrese F, Rossetti AC, Racagni G, Gass P, Riva MA, Molteni R (2014) Brain-derived neurotrophic factor: a bridge between inflammation and neuroplasticity. Front Cell Neurosci 8:430CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Linker RA, Mäurer M, Gaupp S, Martini R, Holtmann B, Giess R, Rieckmann P, Lassmann H, Toyka KV, Sendtner M et al (2002) CNTF is a major protective factor in demyelinating CNS disease: a neurotrophic cytokine as modulator in neuroinflammation. Nat Med 8:620–624CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Banner LR, Patterson PH, Allchorne A, Poole S, Woolf CJ (1998) Leukemia inhibitory factor is an anti-inflammatory and analgesic cytokine. J Neurosci 18:5456–5462CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, Sheridan JF, Godbout JP (2008) Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflammation 5:15CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Nikodemova M, Duncan ID, Watters JJ (2006) Minocycline exerts inhibitory effects on multiple mitogen-activated protein kinases and IkappaBalpha degradation in a stimulus-specific manner in microglia. J Neurochem 96:314–323CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Yoon S-Y, Patel D, Dougherty PM (2012) Minocycline blocks lipopolysaccharide induced hyperalgesia by suppression of microglia but not astrocytes. Neuroscience 221:214–224CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Wang AL, Yu ACH, Lau LT, Lee C, Wu LM, Zhu X, Tso MOM (2005) Minocycline inhibits LPS-induced retinal microglia activation. Neurochem Int 47:152–158CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Scholz R, Sobotka M, Caramoy A, Stempfl T, Moehle C, Langmann T (2015) Minocycline counter-regulates pro-inflammatory microglia responses in the retina and protects from degeneration. J Neuroinflammation 12:209CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Dannhausen K, Möhle C, Langmann T (2018) Immunomodulation with minocycline rescues retinal degeneration in juvenile Neuronal Ceroid Lipofuscinosis (jNCL) mice highly susceptible to light damage. Dis Model Mech 11:dmm.033597CrossRefGoogle Scholar
  128. 128.
    Kohno H, Chen Y, Kevany BM, Pearlman E, Miyagi M, Maeda T, Palczewski K, Maeda A (2013) Photoreceptor proteins initiate microglial activation via Toll-like receptor 4 in retinal degeneration mediated by all-trans-retinal. J Biol Chem 288(21):15326–15341CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Karlstetter M, Nothdurfter C, Aslanidis A, Moeller K, Horn F, Scholz R, Neumann H, Weber BHF, Rupprecht R, Langmann T (2014) Translocator protein (18 kDa) (TSPO) is expressed in reactive retinal microglia and modulates microglial inflammation and phagocytosis. J Neuroinflammation 11:3CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Scholz R, Caramoy A, Bhuckory MB, Rashid K, Chen M, Xu H, Grimm C, Langmann T (2015) Targeting translocator protein (18 kDa) (TSPO) dampens pro-inflammatory microglia reactivity in the retina and protects from degeneration. J Neuroinflammation 12:201CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Doonan F, O’Driscoll C, Kenna P, Cotter TG (2011) Enhancing survival of photoreceptor cells in vivo using the synthetic progestin Norgestrel. J Neurochem 118:915–927CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Jackson ACW, Roche SL, Byrne AM, Ruiz-Lopez AM, Cotter TG (2016) Progesterone receptor signalling in retinal photoreceptor neuroprotection. J Neurochem 136:63–77CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Roche SL, Wyse-Jackson AC, Gómez-Vicente V, Lax P, Ruiz-Lopez AM, Byrne AM, Cuenca N, Cotter TG (2016) Progesterone attenuates microglial-driven retinal degeneration and stimulates protective fractalkine-CX3CR1 signaling. PLoS One 11:e0165197CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Byrne AM, Roche SL, Ruiz-Lopez AM, Jackson ACW, Cotter TG (2016) The synthetic progestin norgestrel acts to increase LIF levels in the rd10 mouse model of retinitis pigmentosa. Mol Vis 22:264–274PubMedPubMedCentralGoogle Scholar
  135. 135.
    Wyse Jackson AC, Cotter TG (2016) The synthetic progesterone Norgestrel is neuroprotective in stressed photoreceptor-like cells and retinal explants, mediating its effects via basic fibroblast growth factor, protein kinase A and glycogen synthase kinase 3β signalling. Eur J Neurosci 43:899–911CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Prinz M, Schmidt H, Mildner A, Knobeloch K-P, Hanisch U-K, Raasch J, Merkler D, Detje C, Gutcher I, Mages J et al (2008) Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity 28:675–686CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Lückoff A, Caramoy A, Scholz R, Prinz M, Kalinke U, Langmann T (2016) Interferon-beta signaling in retinal mononuclear phagocytes attenuates pathological neovascularization. EMBO Mol Med 8:670–678CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Kimoto T, Takahashi K, Tobe T, Fujimoto K, Uyama M, Sone S (2002) Effects of local administration of interferon-beta on proliferation of retinal pigment epithelium in rabbit after laser photocoagulation. Jpn J Ophthalmol 46:160–169CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Tobe T, Takahashi K, Ohkuma H, Uyama M (1995) The effect of interferon-beta on experimental choroidal neovascularization. Nippon Ganka Gakkai Zasshi 99:571–581PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Joshua Kramer
    • 2
  • Kathleen R. Chirco
    • 2
  • Deepak A. Lamba
    • 2
    • 1
    Email author
  1. 1.Department of OphthalmologyUniversity of California San FranciscoSan FranciscoUSA
  2. 2.Buck Institute for Research on AgingNovatoUSA

Personalised recommendations