Treatment of Th1Mediated Autoimmune Skin Diseases Using AntiIFNy

We used anti-IFN-y in patients with psoriasis vulgaris, alopecia areata, vitiligo, acne vulgaris, and herpes simplex type 1, and plan to expand the trials using a humanized monoclonal antibody. Trials are also planned for testing the treatment in other Th-1-mediated skin diseases, including seborrheic dermatitis, rosacea, oral lichen planus, and dermatophyto-sis, which are discussed in the following sections. In most cases, we used two methods of delivery of the antibody: intradermal injection around the lesion and intramuscular administration. Thus, anti-IFN-y delivered to the lesion either IM or locally brought the same effect. We believe anticytokine therapy, particularly the removal or inhibition of IFN-y and/or TNF-a and IL-1, may be a rational treatment for many severe autoimmune skin diseases that do not respond to standard therapies.

1.3.1 Psoriasis Vulgaris

We first proposed that anticytokine therapy could be beneficial in treating psoriasis in 1977 (Skurkovich et al. 1977). Recently in an open-label clinical trial using anti-IFN-y in patients with psoriasis vulgaris using both intramuscular and intradermal injections, we observed very rapid, sometimes striking responses. Seven patients who received IM injections of anti-IFN-y experienced a very rapid reduction of the intensity of the erythema, leading to the disappearance of papular infiltrates and, after a few weeks, clearing of the psoriatic plaques and complete remission in four of the patients (see Fig. 1). Three who still had small infiltrates on the legs were given UV treatments (200-500 nm wavelength), after which two went into full remission and one completed therapy with 80% reduction in plaques (Skurkovich et al. 2002b, 2002c, 2004a). In addition, three patients were given intradermal injections of the antibody fragments (1 ml aliquoted into ten 0.1-ml injections) daily for 7 days around the site and in the center of one lesion. The improvement in these lesions followed a similar course as those of the first seven patients with improvement in nearby untreated lesions noted in some cases. Psoriasis also improved in one patient with psoriasis in addition to type I diabetes when treated with anti-IFN-y for the diabetes. TNF-a antagonists are already used commercially for the treatment of psoriasis but require caution because of possible infectious complications.

Psoriasis is now generally considered to be a Th-1-mediated autoimmune disease, with evidence implicating the proinflammatory cytokines IFN-y and TNF-a (Ozawa and Aiba 2004). IFN-y has also been shown to trigger psoriasis (Fierlbeck et al. 1990), and psoriatic epidermal T cells produce and secrete IFN-y within the lesion (Koga et al. 2002). The level of IFN-y in the sera of psoriasis patients has been found to positively correlate with all indices of disease severity (Jacob et al. 2003).

Anti Interferon Gamma Treatment
Fig. 1. Eleven-year-old patient before treatment with anti-interferon-gamma antibodies (left). Patient 14 days after start of treatment (right)

1.3.2 Alopecia Areata

T-cell clones from alopecia lesions have been reported to release large amounts of IFN-y and/or TNF-a that downregulate epithelial cell proliferation (Thein et al. 1997).

We obtained encouraging results using anti-IFN-y in treating 16 patients (age 6-15 years) with AA in the progressive stage (Skurkovich 2002b, 2002c, 2003c, 2004b; Sharova 2003). Nine had patchy, progressive disease (based on a positive hair pull test at the periphery of the patches), five patients had 100% scalp hair loss, some with eyebrows and/or eyelashes preserved, and two patients had patchy, stable hair loss. Of the 16 patients treated, eight of the nine patients with patchy, progressive hair loss stabilized after 3 days of therapy and showed no additional hair loss. After 4-6 months, these patients showed partial, but on-going (four patients) or full (four patients) terminal, i.e., fully restored, hair-growth, including eyebrows and/or eyelashes, with one having no response (see Fig. 2). By 6 months, only one of these patients had any recurrence (one 1.5-cm lesion that appeared 5 months after

Fig. 2. Left: Fourteen-year-old patient with alopecia areata lasting 4.5 months before intradermal treatment with anti-IFN-y antibodies. Right: Patient 12 weeks after start of treatment

Fig. 2. Left: Fourteen-year-old patient with alopecia areata lasting 4.5 months before intradermal treatment with anti-IFN-y antibodies. Right: Patient 12 weeks after start of treatment treatment), with the rest maintaining or continuing their improvement. Of the five patients with 100% baldness, three had some limited terminal hair growth; the other two showed only vellus hair or no response. Of the two patients with stable but patchy hair loss, one showed complete eyelash and eyebrow hair restoration but both showed no hair growth in the scalp. The eight patients with progressive hair loss were followed for 2 years with two recent relapses. The results support early intervention as most effective in preventing progression to total hair loss. The immediacy and high rate of response to the injections in progressive cases argue against spontaneous remission of the disease as an explanation for the improvement, but larger, controlled trials are planned using a humanized monoclonal antibody.

Since our trial, more experimental evidence has strongly implicated IFN-y in the pathogenesis of AA. Researchers presenting results at the Alopecia Workshop of the 4th Intercontinental Meeting of Hair Research Societies in Berlin, induced AA in wild-type and IFN-y knockout mice by grafting lesional AA skin from alopecia-affected mice. The knockout mice were found to be resistant to the development of AA compared to 90% of the wild-type mice, who developed alopecia. It was hypothesized that, with no IFN-y produced, T-cells were not activated in the knockout mice, confirming that IFN-y may play a key role in activating autoreactive T-cells (Freyschmidt-Paul 2004). Alopecia areata (AA) is now discussed as an autoimmune disease of the hair follicle, especially expressing the Th-1 cytokines interleukin-1P, interleukin-2, and interferon-y (Arca et al. 2004). Progressive AA patients' peripheral blood mononuclear cells display an increased percentage of activated T cells and IL-12 and IFN-y expression (Zoller et al. 2004), a phenomenon frequently observed in autoimmune diseases (Chinon and Shearer 2003).

1.3.3 Vitiligo

Of four vitiligo patients who received intradermal injections around the lesion, two responded with repigmentation in the treated area (Skurkovich et al. 2002b, 2002c, 2003c). In the other two patients, an additional course of intramuscular injections led to a gradual diminishment of the border between the depigmented area and normal skin. Vitiligo lesions also cleared up in a patient treated for AA with anti-IFN-y. As with psoriasis and alopecia, vitiligo is considered a Th-1-mediated autoimmune disease. Perilesional T-cell clones derived from patients with vitiligo show a predominant Th-1-like cytokine secretion profile (Wankowicz-Kalinska et al. 2003), and vitiligo patients demonstrate a statistically significant increase in the expression of IFN-y in involved and adjacent uninvolved skin (Grimes et al. 2004).

1.3.4 Acne Vulgaris

IFN-y may play a central role in the immunopathogenesis of acne (Mouser et al. 2003). The normal skin commensal bacterium Propi-onibacterium acnes (P. acnes), which is implicated in the pathogenesis of inflammatory acne, appears to stimulate a typical Th-1 response. T cell lines from inflamed acne lesions were shown to proliferate in response to P. acnes extract and expressed IFN-y in response to P. acnes stimulation (Mouser et al. 2003).

In a small study, patients with acne vulgaris with multiple infiltrated pustules and elements on the cheeks or forehead were treated with topical anti-IFN-y. A wet gauze compress soaked with anti-IFN-y in liquid form was applied with mild pressure to the affected areas for 1 min, three times a day, for 4 days. By the 2nd day, nearly all pustular elements had dried up with no fresh elements appearing. After 4 days of treatment, the infiltrated elements remained but had paled in color. In another patient, fresh pustules in smaller quantity than before appeared on the 5th day after treatment. Further studies are warranted, and in future, for severe acne, we plan to prepare a complex of anti-IFN-y, an antibiotic, and a retinoid and to test different methods of delivery, including oral, topical, and parenteral.

1.3.5 Herpes Simplex Virus Type 1

Herpes simplex is a common virus affecting the skin, mucous membranes, nervous system, and the eye. Herpes simplex type1 virus has been found to induce certain autoimmune conditions. Autoreactive T cells triggered by herpes simplex type 1 virus play an important role in the pathogenesis of herpes-associated erythema multiforme (HAEM) (Aure-

lian et al. 2003), in which IFN-y is expressed in the lesions (Kokuba et al. 1999). Herpes stromal keratitis, an autoimmune disease characterized by T-cell-dependent destruction of the corneal tissue, is thought to be due to an epitope expressed by a coat protein of the herpes simplex virus being recognized by autoreactive T cells that target corneal antigens in a mouse model (Zhao et al. 1998). Herpes simplex virus type 1 lesions of the mouth and lips may also be Th-1-mediated. In preliminary studies, we found a close association between topical application of anti-IFN-y to herpes lesions and reduction in burning and pain in the lesion area. Thus removal of IFN-y or possibly TNF-a or IL-1 could be beneficial.

Patients with severe, chronic recurring herpes simplex on the lips presenting with erythema and blisters unresponsive to standard treatment were treated with an anti-IFN-y-soaked gauze compress applied to the lesions every 2 h for 1-2 min. After 3-3.5 h, the patients noted rapid reduction of the burning and pain in the area of the lesion. After 2 days, scabs formed, which quickly faded in 5 days. In future, different methods of delivery, including topical (especially on the eyes), oral, and parenteral will be tested.

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Responses

  • olivia mcdonald
    Is lichen planus and acne vulgaris autoimmune disease?
    1 year ago

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