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Manfred Zierhut, Nora Roth, Andreas Korn, Antje Bornemann, Christoph Simon, Annika Böhm, Wolfgang Bethge, Lothar Kanz, Hans-Georg Rammensee, Sebastian Haen; Graft versus Host Disease of the retina and recognition of self-antigens after allogeneic hematopoietic cell transplantation. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):877.
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© ARVO (1962-2015); The Authors (2016-present)
Graft versus Host Disease (GvHD) is believed to be mediated by T cells recognizing major (MHC) or minor histocompatibility antigen mismatches. The exact T cell epitopes recognized on recipient cells remain unknown. Here, we evaluated the GvHD in the posterior eye segment (PS) and the antigens recognized by allogeneic T cells.
Six patients suffered from retinal diseases after HCT, 22 further patients were recruited before HCT irrespective of ocular symptoms. As controls, T cells from 5 family donors and 8 healthy individuals per epitope were evaluated.Autologous DNA was isolated from blood before or oral mucosa cells after HCT. Allogeneic DNA was obtained from blood after HCT (complete donor chimerism). DNA sequencing was used to identify donor-recipient single nucleotide polymorphisms (SNP). Retina specific candidate epitopes derived from the retinal guanylate cyclase 2D (GUCY2D), the retinoid binding protein (RBP) and the guanylate cyclase activating proteins A1 und B1 (GUCA1A/GUCA1B) were predicted based on known SNP and individual gene sequences using the database EpiToolKit. Reactivity of T cells was determined in ELISpot and intracellular cytokine staining.
PS diagnoses were optic nerve atrophy (n=2), in 1 case combined with a selective dysfunction of the cones, optic neuritis (n=2), ischemic retinopathy (n=1) and VZV retinitis (n=1). In 2 of 6 patients specific T cells against GUCY2D epitopes were detected 24 and 40 months after HCT. DNA sequencing did not reveal a SNP indicating recognition of self-antigens. In 6/22 patients without PS symptoms, retina-specific T cells could be detected directed against epitopes derived from GUCA1A (n=3), GUCA1B (n=3) and GUCY2D (n=3) between 4 and 14 months after HCT. Again, no SNP could be observed. Hence, reactivity was directed against self-epitopes. Transplantation of retina-antigen specific cells and reactivity against naturally occurring epitopes were excluded in donors and healthy individuals.
GvHD manifestations of the retina can be detected after allogeneic HCT and mediated by antigen-specific T cells. The antigens recognized hereby can be self-antigens and do not need to be based on SNP between donor and recipient. Development of PS GvHD may be triggered by viral infections and should be considered in case of atypical ophthalmologic findings.
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