The studies performed by Seo et al. (2003) showed that interference in the interactions between CD137 and CD137L abolished the development of Herpetic stromal keratitis (HSK) in a murine model. HSK is an inflammatory disorder characterized by Th 1-mediated destruction of corneal tissues and is induced by HSV-1 infection (Deshpande et al., 2001; Russell et al., 1984). When the corneas of CD137-/- and CD137+/+ littermates on BALB/c background were infected with 1 x 105 PFU of HSV-1 RE strain, the incidence and severity of disease were significantly reduced in CD137-/- compared with CD137+/+ littermates. Leukocyte infiltration in corneas of the CD137-/- mice was absent as well. Similarly, when CD137/CD137L interactions were blocked with multiple doses of anti-CD137L mAb (TKS-1) (Futagawa et al., 2002), the disease development in CD137+/+ mice was also prevented. Herpes-infected CD137+/+ corneas manifested high levels of chemokines and cytokines which are characteristics of activated T cells and monocytes and implicated in HSK pathogenesis. In CD137+/+ mice, majority infiltrating CD3+ T cells in cornea expressed CD137 as well as other T cell activation markers such as CD44, CD25, and CD62L on their surfaces, indicating the possible requirement of CD137 expression for the induction of HSK.
The authors proposed that the CD137 signaling may play a potential role on regulating CD62L (L-selectin) expression. L-Selectin is broadly expressed on most leukocytes and is required for naive lymphocyte homing to secondary lymphoid organs with high endothelial venules (HEV). In addition, it is involved in inflammatory leukocyte trafficking (Rosen, 2004). The lack of CD137/CD137L interactions may result in decreased expression of CD62L on certain T cells, which leads to reduced recruitment of effector T cells into peripheral tissue so that fewer T cells are available in cornea to stimulate inflammation and initiate HSK development. This is based on the facts that CD62L expression on draining lymph node (DLN) CD4+ T cell was significantly less in CD137-/- compared with CD137+/+ mice eight days post infection, a time point when T cells were beginning to infiltrate the corneas, but not at the earlier time points. And CD4+ T cells isolated from DLNs of CD137-/- mice eight days instead of three days PI, manifested diminished migratory potential.
These studies indicate the CD137/CD137L interactions play a critical role in the pathogenesis of HSK through either facilitating the recruitment of pathogenic T cell from the draining lymph nodes to the corneal stroma or promoting the inflammatory responses in local tissue. CD137 signaling targeted immunotherapy may open a new window for treatment of human HSK.
The same group (Seo et al., 2004) also tested the effect of CD137/CD137L pathway blockade on the development of collagen-induced arthritis (CIA), an experimental mouse model for the study of human rheumatoid arthritis (RA), which is a chronic and debilitating inflammatory autoimmune disease of joint (Feldmann et al., 1996). Type-II collagen (CII) is recognized as a prominent target of autoimmune destruction in RA and is the arthritogenic antigen in CIA (Luross and Williams, 2001; Myers et al., 1997). CIA is induced in genetically predisposed mice such as DBA/1 mice by immunization with bovine collagen II (bCII) emulsified in CFA. CD4+ T cells seem to play a central role in disease induction in arthritis (Ranges et al., 1985).
Seo et al. (2004) found that administration of anti-CD137L (TKS-1) resulted in moderately ameliorated arthritis development than that seen with control IgG, and partially inhibited CII-specific CD4+ T cell recall response in CIA model. Such treatment reduced mRNA levels of inflammatory cytokine IL-6 but not IL-1 p and TNF. Compared with agonistic anti-CD137 treatment which we are going to discuss later in this chapter, CD137/CD137L pathway blockade with anti-CD137L showed much milder suppressive effect on CIA. These studies indicate CD137/CD137L interaction may be involved in the activation of arthritogenic T cells.
Was this article helpful?