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Oliver W Gramlich, Qiong Ding, Michael G Anderson, Markus H Kuehn; Adaptive immune responses in glaucoma promote IOP-independent RCG loss. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1694.
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© ARVO (1962-2015); The Authors (2016-present)
To functionally test if immune processes are both initiated and capable of causing damage in glaucoma we carried out adoptive transfers between mouse models of glaucoma and normal recipient mice.
B6.Sh3pxd2bnee (nee), immune-deficient B6.129S7-Rag1tm1Mom/J/nee (nee/Rag1), myocilin transgenic B6.Tg-MYOCY437H (MYOC), or C57BL/6J wild-type (B6) mice served as donors. Splenocytes (5x106) or FACS sorted CD19 (1.5x106) and CD3 (1x106) lymphocyte fractions were transferred to 2-month-old B6 recipients (rec, n>5 animals/group). Intraocular pressure (IOP) was monitored by tonometry and RGC density (RGC/mm2) was evaluated in retinal wholemounts via gamma-synuclein immunostaining. Naïve B6 mice served as a control (ctrl). In additional experiments, OCT imaging was conducted, and transferred immune cells expressing DsRed were spatiotemporally tracked in recipients. Differences were evaluated using Tukey’s post-hoc test.
Transferred splenocytes from both nee or MYOC mice elicit significant loss of RGC in recipient mice after 4 months when compared to ctrl or B6 recipients (RGC/mm2 in ctrl: 2290±254, B6 rec: 2284±299, nee rec: 1886±267, p<0.03; MYOC rec: 1798±152, p<0.02). Transfer of nee/Rag1 splenocytes did not induce loss of RGC (nee/Rag1 rec: 2423±383 RGC/mm2) Animals having received nee T-cells also display significantly reduced RGC density when compared to B6 T-cell recipients (RGC/mm2 in B6 T-cell rec: 2251±221 vs. 1831±245 in nee T-cell rec, p=0.004). Transfer of nee B-cells leads to a modest reduction of RGC (RGC/mm2 in B6 B-cell rec: 2259±266 vs. 1968±317 in nee B-cell rec, p=0.07). Transferred cells were frequently found integrated into the recipients’ spleens. DsRed+ nee lymphocytes were occasionally observed in the retina of recipient mice and appeared to be engaged in cell-cell interaction with microglia. Elevated IOP, disruption of retinal integrity, or significant leukocyte infiltration was not observed in any recipient animals.
These data demonstrate that glaucomatous RCG loss elicits an adaptive immune response that is capable of promoting IOP-independent RGC loss following adoptive transfer. The immunopathology in recipients seems to be primarily T-cell dependent. It is conceivable that once established such an autoimmune response could lead to continued RGC loss in glaucoma patients despite significant reduction in IOP.
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