Humanized anti-CD11a antibody (efalizumab) has been approved by the FDA for the treatment of adults with moderate to severe chronic plaque psoriasis at the time this study was conducted. It had shown efficacy in the treatment of psoriasis, a T-cell-mediated disease. This study is the first to use anti-CD11a in uveitis patients and the first of all biological agents targeted against adhesion molecules to be used in the treatment of uveitis and/or associated macular edema in humans.
Our group had previously shown that interference with adhesion molecule functioning, including CD11a, positively altered the course of disease in animals with experimentally induced uveitis.7
Binding to CD11a on lymphocytes blocked the interaction between LFA-1 and ICAM-1 and, as a result, interrupted lymphocyte migration and inflammation. In this study, the addition of anti-CD11a not only controlled ocular inflammation and aided in the resolution of macular edema, but also allowed patients to reduce the amount of current immunosuppression, reflecting circumstances seen in the laboratory.
Vitreous levels of ICAM-1 have been found to be higher in patients with diabetic macular edema when compared with those in nondiabetic or diabetic patients without retinopathy.23
Dexamethasone has been shown to downregulate ICAM-1 expression in diabetic rats, correlating with its effect on leukocyte accumulation and retinal vascular permeability.24
We propose that targeting CD11a leads to a decrease in T-cell trafficking and adhesion, which is likely to lead to less permeability, less accumulation of macular fluid, and a chance for resorption; hence, patients would have improvement in macular edema and vision.
regulatory NK cells have been proposed to play a regulatory role in immune responses.14,16–18
They have the ability to secrete large amounts of IL-10, an anti-inflammatory cytokine.20
We have previously shown that patients with active uveitis have a significantly lower level of CD56bright
regulatory NK cells than do normal donors.20
In this pilot study, all patients demonstrated an expansion of CD56bright
NK cells, consistent with their clinical picture and previous studies conducted at NEI. Of interest, those with more edema had less expansion. This may represent the difficulty in controlling their disease when compared with those less active. Little is known about the molecular mechanisms of daclizumab (anti-IL2R, or anti-CD25)-induced expansion of the peripheral CD56bright
NK cell population. Our new observation that an anti-CD11a-blocking antibody, can also induce the expansion of the peripheral CD56bright
NK cell population suggests that our previous observation of induction of CD56bright
cells by the humanized anti-CD25 antibody daclizumab may be independent of blockage of the IL-2 receptor. Whether the induction of CD56bright
NK cells is a general phenomenon of humanized antibody therapy is of particular interest. Further studies on other humanized monoclonal antibodies may help to shed light on the nature of this expansion of CD56bright
All our patients tolerated the medication well and did not have any serious side effects. Side effects experienced were those similarly seen with conventional immunosuppressive therapies. Unfortunately, since the completion of this study, efalizumab (Raptiva; Genentech) has been taken off the market due to safety concerns. Three consecutive cases of progressive multifocal leukoencephalopathy (PML) were reported in long-term users of the medication. PML has been reported to occur with other immunosuppressive agents, such as mycophenolate mofetil (Cellcept; Genentech, South San Francisco, CA), that are commonly used for uveitis, but to date no PML has been reported in patients using these agents for uveitis.25
The events associated with efalizumab were typically seen in older patients who had used it for more than a year. One could postulate that since adhesion molecules play an important role in leukocyte recruitment and trafficking,7–12
agents targeting adhesion molecules would be more likely to cause immune function abnormalities that it can normally control. However, not much is known about risk factors associated with PML, and, once diagnosed, the prognosis is poor, making the decision to use efalizumab more difficult. Another monoclonal antibody against an adhesion molecule, natalizumab, has been approved by the FDA for the treatment of multiple sclerosis and, due to its association with PML, strict prescribing criteria have been assigned.
In summary, anti-CD11a therapy was found to be safe and well-tolerated by the patients in this short-term pilot study. Anti-CD11a treatment demonstrated improvement in visual function and macular thickness. Uveitis was controlled and current immunosuppressive regimens were reduced. Larger studies are needed to continue to assess the safety, tolerability, and efficacy of treatments targeting adhesion molecules for macular edema associated with uveitis or other disorders. With more adhesion molecules under investigation and their promising effects on the rise, these agents may eventually find their place in the field of autoimmune disorders with modification in dosing or application.