Ординатура / Офтальмология / Английские материалы / Ocular Therapeutics Eye on New Discoveries_Yorio, Clark, Wax_2007

common gamma chain of the IL-2 receptor. The gamma chain is also shared by IL- 4, IL-7, IL-9, IL-13, and IL-15 (Leonard and O’Shea, 1998). This suggests that inhibitors of JAK3 could intervene not only in conditions where IL-2 activation occurs, but also in conditions where multiple cytokines play a role. In this regard, JAK3 inhibition may rival the broad effects of corticosteroids, but with limited involvement of effects upon non-hematopoietic cells. Because of the effects upon T-cell activation and proliferation, inhibition of JAK3 presents a compelling approach for therapy of AKC and VKC, where T-cells play an important role.

Inhibitors of JAK3 have been produced (Figure 11.9) and tested primarily in models of allograft rejection (Papageorgiou and Wikman, 2004; Thompson, 2005). Positive results have also been reported in a graft versus host disease model of bone marrow

OH

CH3 HN

O

N

H3C

O N

WHIP131

FIGURE 11.9 JAK3 inhibitors

reduced plasma exudation upon antigen challenge. Plasma collected from actively sensitized animals after antigen challenge has been reported to have increased histamine levels. Plasma histamine levels determined in actively sensitized mice were reduced in animals pretreated with the JAK3 inhibitor WHIP131, suggesting that JAK3 inhibition holds potential for effects upon mast cells, as well as T-cell dominated reactions discussed above. Investigation of JAK3 inhibitors for clinical effects in AKC and VKC patients seems warranted.

A discussion of therapies for chronic allergic inflammation must include the

transplantation and autoimmune type-1 diabetes (Cetkovic-Cvrlje et al., 2003).

Interestingly, JAK3 has been discovered in mast cells. Malaviya et al. (2000) harvested bone marrow mast cells from JAK3 knockout mice and wild type mice, passively sensitized them, and challenged them with antigen (DNP-BSA). The investigators measured the amount of LTC4 released into cell-free supernatants. They observed significantly less leukotriene present in mast cells from JAK3 knockout mice than wild type controls. Some of these same authors reported that an inhibitor of JAK3 decreased leukotriene, β-hexosaminidase, and TNFα release from RBL-2H3 cells; and tryptase and leukotriene C4 release from fetal liver derived human mast cells (Malaviya et al., 1999). In vivo administration of the JAK3 inhibitor WHIP131 to sensitized mice significantly

N

N

N

N

NN H

CP690550

two compounds that have been approved by the United States Food and Drug Administration (FDA) for the treatment of VKC. Cromolyn sodium and lodoxamide are compounds commonly referred to as mast cell stabilizers, based upon their activity in rodent and human tryptase containing respiratory mast cell populations. It usually is a surprise to learn that these drugs were never approved for the treatment of SAC or PAC in the United States. However, these drugs are commercially available. The apparent paradox of a “mast cell stabilizer” not being particularly effective in IgE-dependent mast

(Continued)

cell disease (Rimas et al., 1990; Azevedo et al., 1991; Stock and Bielory, 1997) was addressed by demonstrating that cromolyn did not inhibit human conjunctival mast cell histamine release upon immunological stimulation (Yanni et al., 1997). The inability of cromolyn to inhibit mediator release from connective tissue mast cells containing human tryptase and chymase has been reported by others (Okayama and Church, 1992; Okayama et al., 1992). Histamine release studies conducted with cromolyn using tryptase and chymase positive mast cells obtained from human skin failed to demonstrate inhibition of either histamine or prostaglandin D2 release. Concentrations as high as 1mM did not attenuate mediator release. While these studies demonstrate that cromolyn does not stabilize human tryptase and chymase containing mast cells, this drug does possess significant biological activity. Chemotaxis of eosinophils and neutrophils to zymosan- activated-serum and platelet activating factor, respectively, was inhibited by cromolyn

with IC50s of 200nM and 20nM (Bruijnzeel et al., 1990). Cromolyn also is capable of preventing activation of afferent C-fibers and reducing neurogenic edema (Norris, 1996). These anti-inflammatory effects do not involve mast cells, but provide a rationale for clinical benefit observed in VKC (Foster and Duncan, 1980; Leonardi et al., 1987). Similar data exist for lodoaxamide. Capron et al. (1998) reported that the chemotactic responses of eosinophils to fMLP and IL-5 and the release of eosinophil mediators were significantly and dose-dependently inhibited by lodoxoamide. The drug also inhibited ischemia reperfusion-induced microvascular dysfunction. Leukocyte–endothelial cell adhesion and vascular leakage were significantly reduced with either superoxide dismutase or lodoxamide (Kurose et al., 1997). A study conducted in our (JY) laboratory indicated that lodoxamide was a more potent anti-oxidant than vitamin E (Figure 11.10), providing evidence for non-mast cell targeted anti-inflammatory effects.

% Inhibition of lipid degradation

100

Lodoxamide 0.48 ± 0.06 mM

80

60

40

Vitamin E

20

13.6 ± 0.9 mM

0

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