Can we begin to think about immune therapy for diabetes and diabetic retinopathy?

Antiinflammatory therapy is already being evaluated in the treatment of systemic type II diabetes. The evidence suggests that a low-grade inflammatory response in patients with a sedentary lifestyle and a western diet contributes to the development of type II diabetes. Investigators have begun evaluating the use of Salsalate, an NSAID used in the treatment of arthritic pain, in treating difficult-to-control type II diabetes. In a proof of principle study involving 20 patients, Fleischman et al.62 evaluated the effects of Salsalate in a double-masked randomized study. They found that fasting glucose was reduced, as was the glucose level after a glucose challenge. In a randomized study of 54 patients (40 were analyzed), patients receiving Salsalate, 3 g/day for 7 days, once again showed lowered glucose levels. However, the conclusion of these investigators was that the effect was not greater effective insulin activity but rather was due to increased insulin concentrations, which salicylates are known to induce.63 These findings have resulted in a large randomized study supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to evaluate this therapy, which is currently in its active recruitment phase.64

Others have suggested using antidendritic cell therapy for the treatment of systemic diabetes. It is known that mature dendritic cells will serve as antigen-presenting cells to T cells; such antigen transfer would induce an inflammatory response. Such a concept would have potential value in the eye as well.

Another approach for the eye is to use the information gained from both animal and some human studies concerning the upregulation of adhesion molecules in the eye. AntiCD11a antibodies (Raptiva, see Chapter 7), directed against part of the adhesion molecule complex, are being used in uveitis and do appear to have a positive clinical effect. All the information would suggest that interfering with the upregulated response in the eye would be beneficial. However, Raptiva appears to have long-term potential problems that would limit its use at present. Intravitreal application remains to be investigated.

One final word about gene therapy. This area has received much attention, both good and bad. Gene therapy in the eye has certainly attracted interest, with some success. Investigators treating diabetes have thought about this as well, and although it does not directly affect the eye it is possible that altering the systemic course could have a significant effect on the ocular complications.65 These concepts include reducing inflammatory cytokine production, reducing the interaction of antigen-presenting cells with activating T cells, and blocking the interactions that lead to apoptosis of islet cells. We can conceive of similar scenarios in the eye.

Glaucoma

Glaucoma is one of the most common ocular disorders encountered by the eyecare specialist. It has been estimated that by the age of 70, 7% of the population will have glaucoma.66 Glaucoma is clinically thought of a problem of increased intraocular pressure, whereas really it is a

Glaucoma

progressive loss of retinal ganglion cells and their associated axons. Certain ethnic groups appear to have not only a high incidence of the disease but also the most severe disease (for example African-Americans).67–69 Albeit easy to describe when in its full-blown clinical presentation, it has been particularly difficult to develop adequate screening techniques for its detection. The Baltimore Eye Study concluded that there was no cutoff for which reasonable sensitivity and specificity could be obtained.70 It has been reported that 16% of patients will have clinically diagnosed glaucoma without a pressure reading > 21 mmHg.71 The goal of a better understanding of the underlying mechanisms of this disorder so as to develop better ways to screen for the disease and treat it has yet to be reached. One approach is to consider screening the sera of glaucoma suspects for possible immune mediators.

Autoantibodies and glaucoma

Autoantibodies in glaucoma were first reported by Wax et al.72 in patients with normal tension glaucoma. Initial reports centered on antibodies directed against a heat shock protein (HSP 60). Subsequent to these initial observations, antibodies directed against several other proteins have been reported. These include α A and B crystallins and HSP27. HSP 27 antibodies have been reported to induce apoptosis in neuronal cells. Grus and coworkers have also reported antibodies directed against α foldrin, which is a neuronal cytoskeletal protein.73,74 What is particularly interesting about foldrin is that it can be the target of caspase-3, destructive enzymes in the retina that could destroy retinal infrastructural integrity. Further, α foldrin has been implicated in the CNS process leading to Alzheimer’s disease.73,75

Grus and coworkers have evaluated autoantibodies from the sera of patients with normal tension glaucoma (NTG), primary open angle glaucoma (OAG), and controls (Fig. 31-6). The group evaluated the presence of these natural

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Figure 31-6.  Antibody screening techniques in the sera from controls; the antibodies appear to be directed against different antigens compared to sera from patients with normal tension glaucoma and primary open angle glaucoma. (From Grus F, Sun D. Immunological mechanisms in glaucoma. Semin Immunopathol 2008; 30: 121–126.)

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autoantibodies based on their molecular weight and reactivity. They noted that NTG patients had the greatest difference compared to POAG and controls, but POAG patients’ profiles were also different from that seen in healthy controls.

It was thus felt that what is being observed is a dysregulation of the immune system in its normal mechanisms to protect retinal ganglion cells. This concept is illustrated in

Figure 31-7.

The complex natural autoantibody profile found in healthy subjects protects cells from apoptosis or direct attack by antibodies. In patients with autoimmune disease, noxious antibodies are formed and are not counteracted by the protective antibodies. These noxious antibodies may be a result of molecular mimicry – that is, antibodies originally directed against invading organisms whose molecular sequence is similar to the proteins found in retinal ganglion cells. Therefore, the antibodies meant to kill invading cells now kill cells in the retina. It should be emphasized that this is currently a hypothesis.

Cellular immunity and glaucoma

A growing collection of literature is looking at glaucoma no longer as a simple elevation of intraocular pressure but rather as a neuropathy that can be manipulated with neuroprotective measures. Of course, this then requires an understanding of the basic mechanisms that lead to the degenerative changes. One important concept has been particularly championed by Michal Schwartz and coworkers,76 i.e., that lowgrade autoimmune responses are necessary for the continued repair and protection of retinal ganglion cells, and presumably for other cells in the retina as well. Figure 31-8 shows the various factors that could be considered with regard to cellular and cell product mechanisms. Some of the factors that lead to neural degeneration include: oxidative stress and the development of free radicals, which cause damage to the retinal ganglion cell; in addition, although glutamic acid is an important mediator in the neural circuitry, excessive levels are toxic; there may be a lack of neurotropins and

other growth factors in patients with glaucoma; and there is an abnormal accumulation of proteins in the retina of glaucoma patients. Tezel et al.77 showed that oxidatively modified proteins are present during glaucomatous neurodegeneration, proteins similar to what is found in Alzheimer’s disease. Indeed, many of the factors outlined as underlying the pathology leading to glaucoma are seen in neurodegenerative diseases in general.78

These factors lead to the concept that low-grade autoimmunity may result in the protection of these cells. Experiments have supported this. Using a crush injury of the optic nerve, Schwartz and coworkers,76 in a series of papers, showed that the immune system – indeed, T cells – played a key role in protecting the optic nerve. When T cells specific to myelin basic protein are present then the loss of ganglion cells is less after a traumatic nerve injury. Activated T cells provide cytokines and growth factors, and may help stimulate microglia and monocytes. It has been found that myelin-associated antigens only protect white matter (myelinated fibers). In an experiment using the R-16 fragment of IRBP, Bakalash et al.79 showed that this antigen, which normally resides in the retina, could protect retinal ganglion cells. In the case of the IRBP fragment it also induced a uveitis, so the results are both good and bad. However, as a proof of principle it was an important observation. Interestingly, the use of steroids resulted in a further loss of retinal ganglion cells. These observations naturally lead to the question of whether immune intervention would help.

Can immune intervention help alter the course of glaucoma?

At present we have only case reports to support the notion that altering the immune system pharmacologically could be beneficial to glaucoma patients. Fellman et al.80 report the case of a patient with glaucoma who was treated with methotrexate for rheumatoid arthritis. During this period her visual fields improved. In addition, the patient’s serum,