Abstract
Purpose :
Graft-versus-host disease (GVHD) affects ~50% of post-hematopoietic stem cell transplant recipients. This study explores immune-mediated changes in ocular GVHD progression compared to systemic tissues, focusing on distinctive transcriptional changes, particularly in granzyme B (GZMB), TNF-α, and IFN-γ, as contributors to the unique pathogenesis of ocular GVHD.
Methods :
This study used an HLA-matched GVHD mouse model with two groups: (1) T cell and B cell depleted (TBCD-BM) mice without splenocytes; and (2) TBCD-BM mice with splenocytes. Systemic and ocular GVHD severity scores were assessed on days 5, 12, 17, 28, and 37. Mice were sacrificed on days 15, 20, and 40 for ocular and systemic tissue collection. Quantitative PCR analyzed GZMB, TNF-α, and IFN-γ fold changes in the cornea and spleen of each group.
Results :
On day 15, GZMB increased 40-fold in the cornea and 2-fold in the spleen (LFD: 1.3). TNF-α showed no significant change in the cornea and a five-fold increase in the spleen (LFD: 0.7). IFN-γ increased 40-fold in both the cornea and spleen (LFD: 0). On day 20, GZMB showed a 7-fold increase in the cornea and a 2000-fold increase in the spleen (LFD: 2.5). TNF-α increased 7-fold in the spleen for both control and GVHD groups, with no significant change in the cornea (LFD: 0.9). IFN-γ increased 20-fold in the cornea and 80-fold in the spleen (LFD: 0.6). On day 40, GZMB showed a 5-fold change in the cornea and a 10-fold change in the spleen (LFD: 0.3). TNF-α increased 17-fold in cornea for the control group only, while TNF-α decreased to near-negligible levels in the spleen (LFD: 1.3). IFN-γ showed a 20-fold change in the cornea and a 5-fold change in the spleen (LFD: 0.6).
Conclusions :
Transcriptional analysis reveals mechanistic differences in systemic and ocular GVHD, with distinct gene expression patterns in the cornea (ocular) and spleen (systemic). Our results suggests that there is an early cytotoxic T cell response in both the cornea and spleen and the later time points show a more robust cytotoxic T cell response in the eye, consistent with chronic oGVHD. GZMB mediated apoptosis as a result of activated cytotoxic T cells is more significant in the eyes earlier than systemic GVHD but appears to play an important role throughout the development of both systemic and ocular GVHD.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.