Increased Incidence and Accelerated Corneal Allograft Rejection in Mice With Allergic Conjunctivitis Requires Both Th1 and Th2 Cells and the Th1 Cytokine, Interferon-Gamma

Abstract

Purpose:: Allergic conjunctivitis is an important risk factor for corneal allograft rejection. We recently demonstrated that: 1) the Th1 cytokine interferon gamma (IFN-g) is required for maximum expression of allergic conjunctivitis in mice, and 2) both Th1 and Th2 cells are present in rejected corneal allografts in atopic mice but only Th1 cells infiltrated grafts in normal mice. In this study, we examined the roles of IFN-g expression and Th1 and Th2 cells in the exacerbation of corneal allograft rejection in atopic mice.

Methods:: Allergic conjunctivitis was induced in Balb/c mice using either short ragweed (SRW) pollen or ovalbumin (OVA). Mice were treated with anti-IFN-g antibody or an isotype control antibody before and during elicitation of allergic conjunctivitis. C57BL/6 corneal allografts were transplanted to untreated, anti IFN-g-treated and isotype control antibody-treated Balb/c mice. Th1 and Th2 cells were isolated from rejector atopic mice by immunomagnetic bead purification using anti-Tim-3 (Th1 specific) and anti-T1/ST2 (Th2 specific) antibodies. Th1 and Th2 cells, separately or combined, were adoptively transferred to Balb/c nude mice that were then challenged with C57BL/6 corneal allografts.

Results:: Allergic conjunctivitis induced by either SRW pollen or OVA produced a profound increase in the tempo and incidence of corneal allograft rejection (100% rejection for SRW; 90% rejection for OVA; 50% rejection in normal controls; P<0.01 and P = 0.02 respectively). Treatment with IFN-g antibody produced a significant prolongation of corneal allograft survival in mice with allergic conjunctivitis (median graft survival time = 30 days vs 13 days for control mice). Nude mice receiving either Th1 cells or Th2 cells from atopic donors experienced corneal allograft rejection in 40% and 20% of the mice, respectively. By contrast, nude mice receiving both Th1 and Th2 cells together produced 100% corneal allograft rejection.

Conclusions:: Allergic conjunctivitis induced by two independent allergens produced a significant increase in the incidence and tempo of corneal allograft rejection. The Th1 cytokine IFN-g is required for maximal expression of allergic conjunctivitis and exacerbation of corneal allograft rejection. Both Th1 and Th2 cells are required for corneal allograft rejection in atopic mice. Our results imply that Th1 and Th2 cells act cooperatively in the pathophysiology of allergic conjunctivitis and contribute to the accelerated rejection of corneal allografts in atopic mice.

Keywords: transplantation • immunomodulation/immunoregulation • cytokines/chemokines