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Adoptive transfer of immune cells from glaucomatous mice provokes retinal ganglion cell loss in recipients.

Gramlich OW, Ding QJ, Zhu W, Cook A, Anderson MG, Kuehn MH - Acta Neuropathol Commun (2015)

Bottom Line: Signs of pan-retinal inflammation were not detected.Transferred lymphocytes were detected integrated in the spleen and in the retinal ganglion cell layer of recipient animals, albeit at very low frequencies.Furthermore, we observed cell-cell interaction between transferred T-cells and recipient microglia along with focal microglial activation in recipient eyes.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, 52242, IA, USA.

ABSTRACT

Introduction: Several studies have indicated that autoimmune and neuroinflammatory processes contribute to the neurodegeneration of retinal ganglion cells in human glaucoma patients and in animal models. To test the involvement of cellular immune processes in the pathophysiology of retinal ganglion cell degeneration in vivo, we carried out adoptive transfer experiments from two independent genetic mouse models of glaucoma into normal recipient mice.

Results: Our findings indicate that transfer results in a progressive loss of retinal ganglion cells and their axons despite normal intraocular pressure in recipient mice. Signs of pan-retinal inflammation were not detected. Similar findings were obtained following transfer of isolated T-lymphocytes, but not after transfer of splenocytes from immune deficient glaucomatous mice. Transferred lymphocytes were detected integrated in the spleen and in the retinal ganglion cell layer of recipient animals, albeit at very low frequencies. Furthermore, we observed cell-cell interaction between transferred T-cells and recipient microglia along with focal microglial activation in recipient eyes.

Conclusion: This study demonstrates that the pathophysiology of glaucomatous degeneration in the tested animal models includes T-cell mediated events that are capable of causing loss of healthy retinal ganglion cells.

No MeSH data available.


Related in: MedlinePlus

Effects of splenocyte transfer. a Immunohistochemical detection of RGC using gamma-synuclein immunohistochemistry in whole mounted mouse retinae. b IOP data recorded in naïve control mice, nee splenocyte recipient animals two (2 m) and four months (4 m) after transfer, and recipients of healthy B6 splenocyte four months after transfer. IOP in all groups remains within the physiologic range and does not significantly differ between groups (p > 0.07). Data are given as mean ± SD. c RGC density following adoptive transfer in splenocyte recipients and naïve controls. Splenocyte transfer from healthy B6 donors does not affect RGC density in recipient animals (N = 9) four months after transfer. In contrast, animals having received splenocytes from nee donor mice suffer a progressive loss of RGC. Two months (2 m, N = 7) after transfer RGC density in nee splenocyte recipients is slightly reduced, but after four months (4 m, N = 10) approximately 23 % of RGC have been lost. RGC damage is also observed in recipient animals (N = 4) when splenocytes derived from MYOC transgenic mice are transferred. Triangles represent individual RGC data per eye and the horizontal line designates group averages. **Recipient groups vs. naïve control (N = 7), p < 0.01; ##Recipient group vs. B6 recipient animals, p < 0.01; §four month recipient group vs. two month recipient group, p = 0.02. d Average damage scores of optic nerves as determined by PPD staining (1 = healthy optic nerve, 5 = severe damage). Moderate axonal damage is found in optic nerves of nee splenocyte recipients four months after transfer. *nee recipient group vs. naïve control, p = 0.02; #nee recipient group vs. B6 recipient animals, p = 0.02 (Kruskal Wallis test). Data are given as mean ± SD
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Fig1: Effects of splenocyte transfer. a Immunohistochemical detection of RGC using gamma-synuclein immunohistochemistry in whole mounted mouse retinae. b IOP data recorded in naïve control mice, nee splenocyte recipient animals two (2 m) and four months (4 m) after transfer, and recipients of healthy B6 splenocyte four months after transfer. IOP in all groups remains within the physiologic range and does not significantly differ between groups (p > 0.07). Data are given as mean ± SD. c RGC density following adoptive transfer in splenocyte recipients and naïve controls. Splenocyte transfer from healthy B6 donors does not affect RGC density in recipient animals (N = 9) four months after transfer. In contrast, animals having received splenocytes from nee donor mice suffer a progressive loss of RGC. Two months (2 m, N = 7) after transfer RGC density in nee splenocyte recipients is slightly reduced, but after four months (4 m, N = 10) approximately 23 % of RGC have been lost. RGC damage is also observed in recipient animals (N = 4) when splenocytes derived from MYOC transgenic mice are transferred. Triangles represent individual RGC data per eye and the horizontal line designates group averages. **Recipient groups vs. naïve control (N = 7), p < 0.01; ##Recipient group vs. B6 recipient animals, p < 0.01; §four month recipient group vs. two month recipient group, p = 0.02. d Average damage scores of optic nerves as determined by PPD staining (1 = healthy optic nerve, 5 = severe damage). Moderate axonal damage is found in optic nerves of nee splenocyte recipients four months after transfer. *nee recipient group vs. naïve control, p = 0.02; #nee recipient group vs. B6 recipient animals, p = 0.02 (Kruskal Wallis test). Data are given as mean ± SD

Mentions: RGC densities in the recipient animals were determined two (N = 14 eyes) and four months (N = 20 eyes) after nee splenocyte transfer. Data were compared to those derived from mice having received splenocytes from healthy B6 donors (N = 14 eyes) as well as to age-matched naïve control mice i.e. no adoptive transfer (N = 18 eyes). IOP was monitored in all recipients throughout the study and remained in the physiological range in all groups (average: 12.5 ± 2.7 mmHg, p > 0.06, Fig. 1b).Fig. 1


Adoptive transfer of immune cells from glaucomatous mice provokes retinal ganglion cell loss in recipients.

Gramlich OW, Ding QJ, Zhu W, Cook A, Anderson MG, Kuehn MH - Acta Neuropathol Commun (2015)

Effects of splenocyte transfer. a Immunohistochemical detection of RGC using gamma-synuclein immunohistochemistry in whole mounted mouse retinae. b IOP data recorded in naïve control mice, nee splenocyte recipient animals two (2 m) and four months (4 m) after transfer, and recipients of healthy B6 splenocyte four months after transfer. IOP in all groups remains within the physiologic range and does not significantly differ between groups (p > 0.07). Data are given as mean ± SD. c RGC density following adoptive transfer in splenocyte recipients and naïve controls. Splenocyte transfer from healthy B6 donors does not affect RGC density in recipient animals (N = 9) four months after transfer. In contrast, animals having received splenocytes from nee donor mice suffer a progressive loss of RGC. Two months (2 m, N = 7) after transfer RGC density in nee splenocyte recipients is slightly reduced, but after four months (4 m, N = 10) approximately 23 % of RGC have been lost. RGC damage is also observed in recipient animals (N = 4) when splenocytes derived from MYOC transgenic mice are transferred. Triangles represent individual RGC data per eye and the horizontal line designates group averages. **Recipient groups vs. naïve control (N = 7), p < 0.01; ##Recipient group vs. B6 recipient animals, p < 0.01; §four month recipient group vs. two month recipient group, p = 0.02. d Average damage scores of optic nerves as determined by PPD staining (1 = healthy optic nerve, 5 = severe damage). Moderate axonal damage is found in optic nerves of nee splenocyte recipients four months after transfer. *nee recipient group vs. naïve control, p = 0.02; #nee recipient group vs. B6 recipient animals, p = 0.02 (Kruskal Wallis test). Data are given as mean ± SD
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Fig1: Effects of splenocyte transfer. a Immunohistochemical detection of RGC using gamma-synuclein immunohistochemistry in whole mounted mouse retinae. b IOP data recorded in naïve control mice, nee splenocyte recipient animals two (2 m) and four months (4 m) after transfer, and recipients of healthy B6 splenocyte four months after transfer. IOP in all groups remains within the physiologic range and does not significantly differ between groups (p > 0.07). Data are given as mean ± SD. c RGC density following adoptive transfer in splenocyte recipients and naïve controls. Splenocyte transfer from healthy B6 donors does not affect RGC density in recipient animals (N = 9) four months after transfer. In contrast, animals having received splenocytes from nee donor mice suffer a progressive loss of RGC. Two months (2 m, N = 7) after transfer RGC density in nee splenocyte recipients is slightly reduced, but after four months (4 m, N = 10) approximately 23 % of RGC have been lost. RGC damage is also observed in recipient animals (N = 4) when splenocytes derived from MYOC transgenic mice are transferred. Triangles represent individual RGC data per eye and the horizontal line designates group averages. **Recipient groups vs. naïve control (N = 7), p < 0.01; ##Recipient group vs. B6 recipient animals, p < 0.01; §four month recipient group vs. two month recipient group, p = 0.02. d Average damage scores of optic nerves as determined by PPD staining (1 = healthy optic nerve, 5 = severe damage). Moderate axonal damage is found in optic nerves of nee splenocyte recipients four months after transfer. *nee recipient group vs. naïve control, p = 0.02; #nee recipient group vs. B6 recipient animals, p = 0.02 (Kruskal Wallis test). Data are given as mean ± SD
Mentions: RGC densities in the recipient animals were determined two (N = 14 eyes) and four months (N = 20 eyes) after nee splenocyte transfer. Data were compared to those derived from mice having received splenocytes from healthy B6 donors (N = 14 eyes) as well as to age-matched naïve control mice i.e. no adoptive transfer (N = 18 eyes). IOP was monitored in all recipients throughout the study and remained in the physiological range in all groups (average: 12.5 ± 2.7 mmHg, p > 0.06, Fig. 1b).Fig. 1

Bottom Line: Signs of pan-retinal inflammation were not detected.Transferred lymphocytes were detected integrated in the spleen and in the retinal ganglion cell layer of recipient animals, albeit at very low frequencies.Furthermore, we observed cell-cell interaction between transferred T-cells and recipient microglia along with focal microglial activation in recipient eyes.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, 52242, IA, USA.

ABSTRACT

Introduction: Several studies have indicated that autoimmune and neuroinflammatory processes contribute to the neurodegeneration of retinal ganglion cells in human glaucoma patients and in animal models. To test the involvement of cellular immune processes in the pathophysiology of retinal ganglion cell degeneration in vivo, we carried out adoptive transfer experiments from two independent genetic mouse models of glaucoma into normal recipient mice.

Results: Our findings indicate that transfer results in a progressive loss of retinal ganglion cells and their axons despite normal intraocular pressure in recipient mice. Signs of pan-retinal inflammation were not detected. Similar findings were obtained following transfer of isolated T-lymphocytes, but not after transfer of splenocytes from immune deficient glaucomatous mice. Transferred lymphocytes were detected integrated in the spleen and in the retinal ganglion cell layer of recipient animals, albeit at very low frequencies. Furthermore, we observed cell-cell interaction between transferred T-cells and recipient microglia along with focal microglial activation in recipient eyes.

Conclusion: This study demonstrates that the pathophysiology of glaucomatous degeneration in the tested animal models includes T-cell mediated events that are capable of causing loss of healthy retinal ganglion cells.

No MeSH data available.


Related in: MedlinePlus