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Biochemical and immunologic mechanisms in atopic dermatitis: New targets for emerging therapies
REVIEW
ARTICLE
Biochemical and immunologic mechanisms in atopic dermatitis: New targets for emerging therapies Jon M. Hanifin, MD, and Sai Chan, MD Portland, Oregon The immunologic and pharmacophysiologic features of atopic dermatitis have stimulated research seeking to identify relevant effector cells and mediators that characterize chronic skin inflammation. The theory that unifies the various abnormalities associated with atopic dermatitis suggests that hematopoietic cells carrying abnormal genetic expressions of atopy cause clinical disease once they infiltrate the skin and mucosa. The proposed underlying mechanism may be either abnormalities in cyclic nucleotide regulation of marrow-derived cells or allergenic overstimulation that causes secondary abnormalities. The primacy of one mechanism over the other remains unresolved, but this does not obviate their value in identifying two novel therapeutic targets: phosphodiesterase inhibition and immune-intervention alternatives to corticosteroids. New type IV phosphodiesterase inhibitors are proving promising in topical formulations, as are inhibitors of calcineurin, such as FK506 and SDZ ASM 981, an ascomycin macrolactam derivative that in early clinical research appears to offer the potency of a corticosteroid without its adverse side effects. The promising clinical trial profiles of these new topical agents may result in alternative therapies providing potent anti-inflammatory activity without the adverse effects that limit corticosteroid use. (J Am Acad Dermatol 1999;41:72-7.)
A
topic dermatitis (AD) is a chronic cutaneous inflammatory disease that nearly always begins in childhood and follows a remitting/ flaring course that may continue throughout life. An eczematous, severely pruritic disease, AD may be exacerbated by infection, psychologic stress, seasonal/climate changes, irritants, and allergens. The disease often moderates with age, but patients carry a life-long skin sensitivity to irritants and this atopy predisposes them to occupational skin disease. AD is basically an intrinsic inflammatory disease subject to intense flaring in the absence of any discernible environmental exacerbants. This intrinsic trait can be transferred by bone marrow transplantation,1 which confers the recipient with a variety of abnormal immune and inflammatory cells that infiltrate the skin and eventuate in clinical disease. This article reviews the major immunologic and pharmacophysiologic features of AD, the theories of pathogenesis that are emerging from them, and the
From the Department of Dermatology, Oregon Health Sciences University. Reprint requests: Jon M. Hanifin, MD, Professor of Dermatology, (L468), Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd, Portland, OR 97201-3098. Copyright © 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16/1/97913
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ongoing extension of these theories into major new directions in treatment.
IMMUNOLOGIC ABNORMALITIES The histologic feature of AD is the same epidermal spongiosis of any eczematous disease, along with varying degrees of epidermal proliferation (reflecting clinical lichenification), lymphocytic infiltration of predominantly CD4+ T cells into the dermis (and sometimes epidermis), and increased numbers of dermal macrophages and eosinophils.2 A variety of functional abnormalities have been noted in these infiltrating cells as well as in circulating leukocytes.3 These immunologic aberrations have stimulated research along several different investigative pathways, each attempting to distinguish major effector cells from those that tend to characterize chronic inflammatory diseases. IgE-mediated allergic reactivity Most, but not all, persons with AD have a personal or family history of allergic rhinitis or asthma, along with increased serum IgE antibodies against airborne or ingested protein antigens. The earliest investigations focused on type I immediate skin test responses to foods and aeroallergens. These were easily demonstrated, and, with the discovery of IgE, came quantitative evidence that this cytophilic anti-
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body was greatly increased in the serum of most patients with AD. These striking associations have stimulated nearly 80 years of research, much of it procrustean attempts to relate IgE to the pathogenic mechanisms that result in eczematous lesions of AD. However, 20% of patients with AD have normal serum IgE and no allergen reactivity,4,5 and the disease also occurs in agammaglobulinemic children with no IgE.6 Patients treated with recombinant interferon gamma improve in the face of escalating serum IgE levels.7 AD usually diminishes during the spring hayfever season, when aeroallergens are at maximum concentrations. Thus the role of IgE in this eczematous cutaneous disease remains tenuous and speculative. Cellular immune abnormalities Early clinicians, including Kaposi, were aware of some immune incompetence in patients with AD, as reflected in susceptibility to widespread herpes simplex infections.8 Later observers noted reduced sensitivity of patients with AD to poison ivy and dinitrochlorobenzene, leading to in vitro lymphocyte proliferation studies that likewise showed impaired sensitization responses.9 The immunohistochemical similarities of AD to contact allergy raised a paradox: Lesions that appear to reflect cell-mediated immunity occur in skin with reduced cellular immune responses.10 This paradox has been clarified considerably during the past 8 years by the concept of a Th1/Th2 immunologic dichotomy. In 1990, Reinhold et al11 demonstrated reduced interferon gamma (IFN-γ) production by peripheral blood mononuclear cells of patients with AD; subsequent studies showed increased interleukin (IL)-4 production by atopic T cells in vitro.12,13 Direct assessment of cells in AD skin lesions was less clear-cut. Immunocytochemistry has suggested a two-phase process, with initial predominance of Th2 cells expressing IL-4, replaced by Th1 cells expressing IFN-γ.14 The original expectation of IL-4/IFN-γ polarity between AD and allergic contact dermatitis (ACD) did not bear out under assessment of cytokine profiles; IFN-γ expression was as prominent as IL-4 in AD lesions, whereas IL-4 expression was seen in some cases of ACD.15 The probable conclusion from these various studies is that in vivo cellular expression of cytokines is highly variable amidst a melange of inflammatory factors. The most consistent result from lesional studies has been the increased expression of IL-10, mirrored by clearly increased spontaneous production of IL-10 by AD monocytes in vitro.15,16 The discovery of increased IL-10 production provides a rational explanation for the paradox of
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the increased and decreased cellular immune responses in AD. The suppressive effect of IL-10 on Th1 cell proliferation and function is well accepted, and in vitro studies indicate that monocytes might cause the decreased IFN-γ production by T cells from patients with AD.17 The therapeutic efficacy of systemic IL-10 in psoriasis, a condition of decreased IL-10 expression levels that now appears to be at the opposite pole from AD,16 highlights the potentially important pathogenic role that monocyte factors such as IL-10 can play in chronic inflammatory disease. Dendritic cells Considerable interest in recent years has focused on the possible pathogenic role of Langerhans cells (LCs) in AD. Increased numbers of these cells are seen in chronic AD lesions18; Bruynzeel-Koomen et al19 later demonstrated that more of these cells carried cytophilic IgE antibodies. Those observations led to the demonstration of FcεRII (CD23) expression and to the demonstration of FcεRI high-affinity IgE receptors on LCs and monocytes from patients with AD.20 Studies have shown that lesional LCs are hyperstimulatory for autologous T cells21 and that aeroallergen-specific IgE can increase the antigen-presenting function of LCs in patients with AD.22 These findings suggest a possible mechanism by which IgE might contribute to the abnormal cellular immune and eczematous responses seen in AD. Eosinophils The consistent presence of eosinophils in AD lesions lay hidden until 1985, when Leiferman et al23 detected their presence, often in a degradative state, through the use of labeled antibodies against eosinophil-specific major basic protein (MBP). Eosinophil proteins such as MBP and eosinophil cationic protein (ECP) are toxic substances that could themselves create the inflammatory milieu that manifests clinically as AD. Studies showing increased MBP in skin biopsy specimens after positive food challenge reactions are a major source of support for the etiologic role of food allergy in eczematous AD lesions.24 In the past year, Beck et al25 have shown that persons with clinical allergic respiratory disease have a greater eosinophilic response to intradermal injections of the eosinophil-tactic cytokine RANTES. Recent studies have also indicated that the production of eotaxin, another protein chemotactic for eosinophils, is induced in IL-4-treated fibroblasts in vitro.26 These studies provide substantial evidence for the role of eosinophils as major effector cells in AD.
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PHARMACOPHYSIOLOGIC ABNORMALITIES Clinical observations of patients with AD have pointed to many physiologic and pharmacologic aberrations, including acral vasodilatation, positive cold-pressor test, white dermographism, and a peculiar delayed blanch response to intradermal acetylcholine and methacholine.27 Similarly, patients with reactive airways or asthma overreact to inhaled methacholine, a response widely used to diagnose susceptibility to asthma.28 Such observations moved Szentivanyi29 to suggest in 1968 that atopic patients behaved as though they had a “blockade” of β-adrenergic receptors, causing a cholinergic overbalance. He proposed that atopy is a disease of over-reactive pharmacologic reactivity. Immunologic reactions would be only one group along with infections, chemical, physical and psychic stimuli, which might trigger the pathologic hyper-reactivity. His work led to in vitro assessments of cyclic AMP (cAMP) responses in peripheral leukocytes, which showed deficient cAMP responses to β-adrenergic agents in AD leukocyte cell cultures.30 The clue that this defect was not limited to the β-adrenergic receptor was the finding that similarly deficient cAMP responses occurred with stimulation by other adenylyl cyclase agonists such as prostaglandin E2 and histamine.31 The defect must therefore be further down the stimulatory pathway. This revelation led to demonstration of increased cAMP hydrolysis by overly active phosphodiesterase (PDE) isoforms in atopic leukocytes.32,33
TOWARD A PATHOPHYSIOLOGIC PARADIGM These studies collectively provided a basis for unifying the immunologic and pharmacophysiologic defects that are so ubiquitous in AD leukocytes and in the clinical disease. Another key to our understanding of this wide-based regulatory dysfunction was the demonstration that atopy, including airway reactivity, eczema, and antigen-specific IgE reactivity, could be transferred by bone marrow transplantation.1 Thus abnormal expression of probably multiple, atopy-associated genes is carried by hematopoietic cells that, when they infiltrate skin and mucosal sites, react inappropriately to cause clinical disease. This information has led to the development of two pathophysiologic paradigms: one centered on fundamental abnormalities in cyclic nucleotide regulation of marrow-derived cells, and the other on the belief that allergenic overstimulation causes secondary immunologic and pharmacophysiologic abnormalities.
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cAMP PDE abnormalities In this hypothesis, the core deficit in atopy lies in genetically defined PDE isoforms that lead to inadequate cellular cAMP levels. Because cAMP normally causes negative modulation of immune and inflammatory responses, inflammatory cells fail to shut off normally. This hyperreactivity culminates in what we see in atopy—excess reactivity to irritants, infectious agents, and antigens that includes increased production of IL-4 and IgE, monocyte secretion of IL-10 and prostaglandin E2, and excessive release of histamine by mast cells and basophils.3 This more comprehensive paradigm explains the dominant nonimmunologic characteristics of AD such as hyperirritancy and reactive airway disease, even in those 20% of patients lacking allergic IgE reactivity.28,34 The allergy hypothesis This hypothesis holds that early (perhaps even in utero) antigenic exposures cause the genetically susceptible person to proliferate antigenically stimulated Th2-dominant T-cell clones, which elaborate IL-4, IL5, IL-6, IL-10, and IL-13 on re-exposure to the antigen. These factors, in turn, stimulate excessive IgE production by the B cell and a tendency to eosinophilrich inflammation. This creates a milieu for mast cellinitiated inflammation that, if repeated over a long period, can produce eczematous disease, asthma, and allergic rhinitis. According to this hypothesis, decreased cyclic nucleotide production by stimulated leukocytes represents a secondary effect of this immunologic stimulation, although it has not yet been possible to generate the specific atypical PDE isoforms by in vitro perturbations.
EXTENDING THEORIES TO THERAPY These theories represent classic “chicken and egg” conflicts; controversies will no doubt reign until the atopic diseases are defined at a molecular genetic level. In the meantime, we can still utilize the information that we have to seek therapeutically approachable targets. In fact, the two pathophysiologic paradigms of cAMP/PDE abnormalities and allergy have given rise over recent years to two novel therapeutic approaches to AD: PDE inhibition and immune intervention. PDE inhibition PDE inhibitors target the cyclic nucleotide abnormalities characteristic of AD (Fig 1). Drugs such as theophylline and other agents have been used for many years in the treatment of asthma. However, theophylline lacks sufficient potency to have much
Hanifin and Chan 75
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B A
Fig 1. A, Adenylyl cyclase stimulatory agents (eg, epinephrine, prostaglandin E2, histamine) bind their respective receptors to generate cAMP production, which in turn activates protein kinase A (PKA), inhibiting protein kinase C (PKC). B, This reduces mediator release and the other leukocyte functions shown here. PDE activity, which is increased in atopic leukocytes, causes increased release of a variety of mediators and cytokines. Each of these cell functions is reduced by PDE inhibitors.
effect in AD, and systemic treatment with newer, more potent PDE inhibitors has been associated with a high incidence of nausea and vomiting.35 Topical caffeine showed efficacy in one study, but the compound was weak and cosmetically unacceptable.36 Newer type IV PDE inhibitors have evolved through the years and are coming under increased research scrutiny for asthma and AD.37 Ro 20-1724 as a 1% cream was shown to be about as effective as 1% hydrocortisone cream, but the compound was not developed further. More recently, our group screened several compounds for in vitro potency and identified one (CP-80633) that is 3 logs more potent than theophylline.38 It provided rapid and persistent anti-inflammatory activity when applied as a 0.5% cream to AD lesions, with no adverse reactions.38 This drug is currently under development and other even more potent PDE inhibitors can be anticipated in coming years. Disease-modifying immune intervention Immunosuppressive agents have traditionally included steroids, azathioprine, and methotrexate. In this discussion, we will focus on the new, more selective drugs for immune intervention. These structurally distinct compounds all bind to unrelated cytosolic binding proteins, known as immunophilins,39,40 but have a common result: the formation of inhibitory complexes that block calcineurin phosphatase activity, which, in turn, inhibits initiation of cytokine transcription and activation of T cells (Fig 2). Drugs that act by this mechanism and are currently under varying stages of clinical development include oral cyclosporine and topical macrolactam
Fig 2. Cyclosporine and FK506 bind their respective phosphatase-binding sites (cyclophilin and FK-binding protein 12 [FKBP12]), blocking action of nuclear factor in activated T cells (NF-AT) and, in turn, inhibiting cytokine (eg, IL-4) gene activation.
agents, such as FK506, and the ascomycin derivative SDZ ASM 981. Oral cyclosporine has been explored during the past 10 years for the treatment of AD and psoriasis, and its efficacy supports the view that these diseases are characterized by T-cell activation. However, concern about systemic side effects, especially renal toxicity, has limited the use of this drug to all but the most severe and refractory patients. Attempts to administer cyclosporine topically in both AD and psoriasis have failed, presumably because of poor percutaneous penetration.41 Another calcineurin inhibitor used to prevent transplant rejection, FK506, is 10 to 100 times more
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potent than cyclosporine in inhibiting T-cell activation.40,42 Its topical application has been shown to be effective in animal models of inflammation as well as in short-term clinical trials in AD.42-44 FK506 ointment is absorbed passively through the skin, with only a small fraction of the drug entering the systemic circulation.45 Phase I data using 0.3% FK506 ointment indicate that systemic absorption of the drug is low and decreases as local inflammatory conditions improve. Furthermore, the drug does not appear to accumulate in the skin or in the systemic circulation after repeated topical administration.45 Although initial application site burning and itching still occur, no systemic side effects have been reported in short-term clinical trials, and additional trials of this promising agent are under way.46 The newest drugs for immune intervention are the inflammatory cytokine inhibitors derived from the macrolactam ascomycin. SDZ ASM 981 is the most advanced in development. When applied topically in preclinical models, SDZ ASM 981 proved to be as potent as the corticosteroid clobetasol, without its local side effects.47 In addition, SDZ ASM 981—in contrast to cyclosporine and FK506— showed only a low potential for systemic immunosuppression when administered orally.47 The clinical efficacy and safety of SDZ ASM 981 have been confirmed in short-term trials in patients with moderate AD.48 Twice-daily applications were well tolerated, with no systemic adverse reactions. Although localized burning and stinging, resembling reactions to topical FK506, occurred, there was no skin atrophy, such as often occurs after use of topical corticosteroids. Systemic exposure after topical administration was low, with blood concentrations of the drug after repeated applications in patients with AD proving similar to those following a single application in healthy volunteers.47,48 This promising preclinical and early clinical profile suggests that the topical macrolactam immunosuppressants may offer the potent activity of a topical corticosteroid, without local side effects, such as skin atrophy.49 Additional clinical investigations are ongoing. Long-term safety evaluations of both FK506 and SDZ ASM 981 will be important in defining the future of these much-needed drugs for treating patients with AD.
CONCLUSION Novel therapies, including PDE inhibitors and new drugs for disease-modifying immune-intervention out of the group of ascomycins and FK506, provide a revolutionary approach to treatment of AD, allowing us to sidestep controversies of pathogenesis and to focus on potent benefit to our patients.
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During 4 decades, we have been limited largely to oral and topical glucocorticosteroid drugs that conferred increased toxicity parallel to increased potency of new compounds. As the new macrolides and PDE inhibitors become available, we must recall the corticosteroid example and realize that adverse effects, especially with topical agents, may not be detected until the drugs have been used for a year or more. Barring major complications, however, the advent of new effective agents will provide alternatives to corticosteroid monotherapy that will allow cycles of two or more drug treatment regimens that can reduce the magnitude of steroid toxicity. This can be of great value, especially in allowing treatment of steroid-sensitive areas such as the face and neck, and caring safely for children.45 Steroid-sparing alternative regimens that have provided more effective rotational therapy for psoriasis in recent years would appear to be approaching reality for AD as well. REFERENCES 1. Agosti JM, Sprenger JD, Lum LG, Witherspoon RP, Fisher LD, Storb R, et al. Transfer of allergen-specific IgE-mediated hypersensitivity with allogeneic bone marrow transplantation. N Engl J Med 1988;319:1623-8. 2. Thepen T, Langeveld-Wildschut G, Bihari IC, Van Wichen DF, Van Reijsen FC, Mudde GC. Biphasic response against aeroallergen in atopic dermatitis showing a switch from an initial TH2 response to a TH1 response in situ: an immunocytochemical study. J Allergy Clin Immunol 1996;97:828-37. 3. Hanifin JM, Chan SC. Monocyte phosphodiesterase abnormalities and dysregulation of lymphocyte function in atopic dermatitis. J Invest Dermatol 1995;105(suppl):84S-88S. 4. Ohman S, Johansson SG. Immunoglobulins in atopic dermatitis. Acta Derm Venereol (Stockh) 1974;54:193. 5. Jones HE, Inouye JC, McGerity JL, Lewis CW. Atopic disease and serum immunoglobulin-E. Br J Dermatol 1975;92:17-25. 6. Peterson RD, Page AR, Good RA. Wheal and erythema allergy in patients with agammaglobulinemia. J Allergy 1966;33:406-11. 7. Hanifin JM, Schneider LC, Leung DYM, Ellis CN, Jaffe HS, Izu AE, et al. Recombinant interferon-gamma therapy for atopic dermatitis. J Am Acad Dermatol 1993;28:189-97. 8. Hanifin JM, Lobitz WC. Newer concepts of atopic dermatitis. Arch Dermatol 1977;113:663-70. 9. Elliott ST, Hanifin JM. Delayed cutaneous hypersensitivity and lymphocyte transformation: dissociation in atopic dermatitis. Arch Dermatol 1979;115:36-9. 10. Zachary CB, Allen MH, MacDonald DM. In situ quantification of T-lymphocyte subsets and Langerhans cells in the inflammatory infiltrate of atopic eczema. Br J Dermatol 1985;112:149-56. 11. Reinhold U, Wehrmann W, Kukel S, Kreysel HW. Recombinant interferon-γ in severe atopic dermatitis. Lancet 1990;1:1282. 12. Jujo KH, Renz J, Abe EW, Leung DY. Decreased interferongamma and increased interleukin 4 production in atopic dermatitis promotes IgE synthesis. J Allergy Clin Immunol 1992;90:323-31. 13. Chan SC, Li S-H, Hanifin JM. Increased interleukin 4 production by atopic mononuclear leukocytes correlates with increased cyclic AMP-PDE activity and is reversible by PDE inhibition. J Invest Dermatol 1993;100:681-4.
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14. Grewe M, Walther S, Gyufko K, Czech W, Schopf E, Krutmann J. Analysis of the cytokine pattern expressed in situ in inhalant allergen patch test reactions of atopic dermatitis patients. J Invest Dermatol 1995;105:407-10. 15. Ohmen JD, Hanifin JM, Nickoloff BJ, Rea TH, Wyzykowski R, Kim J. Overexpression of IL-10 in atopic dermatitis: contrasting cytokine patterns with delayed-type hypersensitivity reactions. J Immunol 1995;154:1956-63. 16. Asadullah K, Sterry W, Stephanek K, Jasulaitis D, Leupold M, Audring H. IL-10 is a key cytokine in psoriasis: proof of principle by IL-10 therapy: a new therapeutic approach. JClin Invest 1998;101:783-94. 17. Chan SC, Kim J-W, Henderson WR Jr, Hanifin JM. Altered prostaglandin E2 regulation of cytokine production in atopic dermatitis. J Immunol 1993;151:3345-52. 18. Uno H, Hanifin JM. Langerhans cells in acute and chronic epidermal lesions of atopic dermatitis, observed by L-Dopa histofluorescence, glycol methacrylate thin section, and electron microscopy. J Invest Dermatol 1980;75:52-60. 19. Bruynzeel-Koomen CA, van Wichen DF, Toonstra J, Berrens L, Bruynzeel PL. The presence of IgE molecules on epidermal Langerhans cells in patients with atopic dermatitis. Arch Dermatol Res 1986;278:199-205. 20. Bieber T, de la Salle C,Wollenberg A, Chizzonite R, Hakimi J, et al. Human Langerhans cells express the high-affinity receptor for immunoglobulin E. J Exp Med 1992;175:1285-90. 21. Taylor RS, Baadsgaard O, Hammerberg C, Cooper KD. Hyperstimulatory CD1a+CD1b+CD36+ Langerhans cells are responsible for increased autologous T lymphocyte reactivity to lesional epidermal cells of patients with atopic dermatitis. JImmunol 1991;147:3794-802. 22. Mudde GC,Van Reijsen FC, Boland GJ, De Gast GC, Bruijnkeel PL, Bruijnkeel-Koomen CA. Allergen presentation by epidermal Langerhans cells from patients with atopic dermatitis is mediated by IgE. Immunology 1990;69:335-41. 23. Leiferman KM, Ackerman SJ, Sampson HA, Haugen HS,Venencie PY, Gleich GJ. Dermal deposition of eosinophil-granule major basic protein in atopic dermatitis. N Engl J Med 1985;313:28285. 24. Ott NL, Gleich GJ, Peterson EA, Fujisawa T, Sur S, Leiferman KM. Assessment of eosinophil and neutrophil participation in atopic dermatitis: comparison with the IgE-mediated latephase reaction. J Allergy Clin Immunol 1994;94:120-8. 25. Beck LA, Dalke S, Leiferman KM, Bickel CA, Hamilton R, Rosen H. Cutaneous injection of RANTES causes eosinophil recruitment: comparison of nonallergic and allergic human subjects. J Immunol 1997;159:2962-72. 26. Mochizuki M, Bartels J, Mallet AI, Christophers E, Schroder JM. IL4 induces eotaxin: a possible mechanism of selective eosinophil recruitment in Helminth infection and atopy. JImmunol 1998;160:60-8. 27. Hanifin JM. Pharmacophysiology of atopic dermatitis. Clin Rev Allergy 1986;4:43-65. 28. Barker AF, Hirshman CA, D’Silva R, Hanifin JM. Airway responsiveness in atopic dermatitis. JAllergy Clin Immunol 1991;87: 780-3. 29. Szentivanyi A. The beta-adrenergic theory of the atopic abnormality in bronchial asthma. JAllergy 1968;42:203-32. 30. Parker CS, Eisen AZ. Altered cyclic-AMP metabolism in atopic eczema. Clin Res 1972;20:418. 31. Safko MJ, Chan SC, Cooper KD, Hanifin JM. Heterologous desensitization of leukocytes: a possible mechanism of beta adrenergic blockade in atopic dermatitis. J Allergy Clin Immunol 1981;68:218-25.
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32. Grewe SR, Chan SC, Hanifin JM. Elevated leukocyte cyclic AMPphosphodiesterase in atopic disease: a possible mechanism for cyclic AMP-agonist hyporesponsiveness. JAllergy Clin Immunol 1982;70:452-7. 33. Chan SC, Reifsnyder D, Beavo JA, Hanifin JM. Immunochemical characterization of the distinct monocyte cyclic AMP-phosphodiesterase from patients with atopic dermatitis. JAllergy Clin Immunol 1993;91:1179-88. 34. Nassif A, Chan SC, Storrs FJ, Hanifin JM. Abnormal skin irritancy in atopic dermatitis and in atopy without dermatitis. Arch Dermatol 1994;130:1402-7. 35. Torphy TJ, Undem BJ. Phosphodiesterase inhibitors: new opportunities for the treatment of asthma. Thorax 1991;46:512-23. 36. Kaplan RJ, Daman L, Rosenberg EW, Feigenbaum S. Topical use of caffeine with hydrocortisone in the treatment of atopic dermatitis. Arch Dermatol 1978;114:60-2. 37. Houslay MD, Sullivan M, Bolger GB. The multienzyme PDE4 cyclic adenosine monophosphate-specific phosphodiesterase family: intracellular targeting, regulation, and selective inhibition by compounds exerting anti-inflammatory and antidepressant actions. Adv Pharmacol 1998;44:225-342. 38. Hanifin JM, Chan SC, Cheng JB, Toffe SJ, Henderson WR Jr, Kirby DS, et al. Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis. J Invest Dermatol 1996;107:51-6. 39. Ho S, Clipstone N, Timmerman L, Northrop J, Graef I, Fiorentino D, et al. The mechanism of action of cyclosporin A and FK506. Clin Immunol Immunopathol 1996;80:S40-S45. 40. Bieber T. Topical tacrolimus (FK 506): a new milestone in the management of atopic dermatitis. J Allergy Clin Immunol 1998;102:555-7. 41. De Rie MA, Meinardi MHM, Dos J. Lack of efficacy of topical cyclosporin A in atopic dermatitis and allergic contact dermatitis. Acta Derm Venereol (Stockh) 1991;71:452-4. 42. Ruzicka T, Bieber T, Schöpf E, Rubins A, Dobozy A, Bos JD, et al (for the European Tacrolimus Multicenter Atopic Dermatitis Study Group). A short-term trial of tacrolimus ointment for atopic dermatitis. NEngl J Med 1997;337:816-21. 43. Aoyama H, Tabata N, Tanaka M, Vesugi Y, Tagami H. Successful treatment of resistant facial lesions of atopic dermatitis with 0.1% FK506 ointment. Br J Dermatol 1995;133:494-6. 44. Nakagawa H, Etoh T, Ishibashi Y, et al. Effects of tacrolimus (FK506) ointment for facial atopic dermatitis. Allergy 1995; 50:368. 45. Alaiti S, Kang S, Fiedler VC, et al.Tacrolimus (FK506) ointment for atopic dermatitis: a phase I study in adults and children. J Am Acad Dermatol 1998;38:69-76. 46. Boguniewicz M, Fiedler VC, Raimer S, Ellis CN, Spurlin DV, Fader D, et al. A randomized vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children. J Allergy Clin Immunol 1998;102:635-42. 47. Meingassner JG, Grassberger M, Fahrngruber H, Moore HD, Schuurman H, Stutz A. A novel anti-inflammatory drug, SDZ ASM 981, for the topical and oral treatment of skin diseases: in vivo pharmacology. Br J Dermatol 1997;137:568-76. 48. Van Leent EJ, Graber M, Thurston M, Wagenaar A, Spuls PI, Bos JD. Effectiveness of the ascomycin macrolactam SDZ ASM 981 in the topical treatment of atopic dermatitis. Arch Dermatol 1998;134:805-9. 49. Reitamo S, Rissanen J, Remitz A, Granlund H, Erkko P, Elg P, et al. Tacrolimus ointment does not affect collagen synthesis: results of a single-center randomized trial. J Invest Dermatol 1998; 111:396-8.
ARTICLE
Biochemical and immunologic mechanisms in atopic dermatitis: New targets for emerging therapies Jon M. Hanifin, MD, and Sai Chan, MD Portland, Oregon The immunologic and pharmacophysiologic features of atopic dermatitis have stimulated research seeking to identify relevant effector cells and mediators that characterize chronic skin inflammation. The theory that unifies the various abnormalities associated with atopic dermatitis suggests that hematopoietic cells carrying abnormal genetic expressions of atopy cause clinical disease once they infiltrate the skin and mucosa. The proposed underlying mechanism may be either abnormalities in cyclic nucleotide regulation of marrow-derived cells or allergenic overstimulation that causes secondary abnormalities. The primacy of one mechanism over the other remains unresolved, but this does not obviate their value in identifying two novel therapeutic targets: phosphodiesterase inhibition and immune-intervention alternatives to corticosteroids. New type IV phosphodiesterase inhibitors are proving promising in topical formulations, as are inhibitors of calcineurin, such as FK506 and SDZ ASM 981, an ascomycin macrolactam derivative that in early clinical research appears to offer the potency of a corticosteroid without its adverse side effects. The promising clinical trial profiles of these new topical agents may result in alternative therapies providing potent anti-inflammatory activity without the adverse effects that limit corticosteroid use. (J Am Acad Dermatol 1999;41:72-7.)
A
topic dermatitis (AD) is a chronic cutaneous inflammatory disease that nearly always begins in childhood and follows a remitting/ flaring course that may continue throughout life. An eczematous, severely pruritic disease, AD may be exacerbated by infection, psychologic stress, seasonal/climate changes, irritants, and allergens. The disease often moderates with age, but patients carry a life-long skin sensitivity to irritants and this atopy predisposes them to occupational skin disease. AD is basically an intrinsic inflammatory disease subject to intense flaring in the absence of any discernible environmental exacerbants. This intrinsic trait can be transferred by bone marrow transplantation,1 which confers the recipient with a variety of abnormal immune and inflammatory cells that infiltrate the skin and eventuate in clinical disease. This article reviews the major immunologic and pharmacophysiologic features of AD, the theories of pathogenesis that are emerging from them, and the
From the Department of Dermatology, Oregon Health Sciences University. Reprint requests: Jon M. Hanifin, MD, Professor of Dermatology, (L468), Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd, Portland, OR 97201-3098. Copyright © 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16/1/97913
72
ongoing extension of these theories into major new directions in treatment.
IMMUNOLOGIC ABNORMALITIES The histologic feature of AD is the same epidermal spongiosis of any eczematous disease, along with varying degrees of epidermal proliferation (reflecting clinical lichenification), lymphocytic infiltration of predominantly CD4+ T cells into the dermis (and sometimes epidermis), and increased numbers of dermal macrophages and eosinophils.2 A variety of functional abnormalities have been noted in these infiltrating cells as well as in circulating leukocytes.3 These immunologic aberrations have stimulated research along several different investigative pathways, each attempting to distinguish major effector cells from those that tend to characterize chronic inflammatory diseases. IgE-mediated allergic reactivity Most, but not all, persons with AD have a personal or family history of allergic rhinitis or asthma, along with increased serum IgE antibodies against airborne or ingested protein antigens. The earliest investigations focused on type I immediate skin test responses to foods and aeroallergens. These were easily demonstrated, and, with the discovery of IgE, came quantitative evidence that this cytophilic anti-
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body was greatly increased in the serum of most patients with AD. These striking associations have stimulated nearly 80 years of research, much of it procrustean attempts to relate IgE to the pathogenic mechanisms that result in eczematous lesions of AD. However, 20% of patients with AD have normal serum IgE and no allergen reactivity,4,5 and the disease also occurs in agammaglobulinemic children with no IgE.6 Patients treated with recombinant interferon gamma improve in the face of escalating serum IgE levels.7 AD usually diminishes during the spring hayfever season, when aeroallergens are at maximum concentrations. Thus the role of IgE in this eczematous cutaneous disease remains tenuous and speculative. Cellular immune abnormalities Early clinicians, including Kaposi, were aware of some immune incompetence in patients with AD, as reflected in susceptibility to widespread herpes simplex infections.8 Later observers noted reduced sensitivity of patients with AD to poison ivy and dinitrochlorobenzene, leading to in vitro lymphocyte proliferation studies that likewise showed impaired sensitization responses.9 The immunohistochemical similarities of AD to contact allergy raised a paradox: Lesions that appear to reflect cell-mediated immunity occur in skin with reduced cellular immune responses.10 This paradox has been clarified considerably during the past 8 years by the concept of a Th1/Th2 immunologic dichotomy. In 1990, Reinhold et al11 demonstrated reduced interferon gamma (IFN-γ) production by peripheral blood mononuclear cells of patients with AD; subsequent studies showed increased interleukin (IL)-4 production by atopic T cells in vitro.12,13 Direct assessment of cells in AD skin lesions was less clear-cut. Immunocytochemistry has suggested a two-phase process, with initial predominance of Th2 cells expressing IL-4, replaced by Th1 cells expressing IFN-γ.14 The original expectation of IL-4/IFN-γ polarity between AD and allergic contact dermatitis (ACD) did not bear out under assessment of cytokine profiles; IFN-γ expression was as prominent as IL-4 in AD lesions, whereas IL-4 expression was seen in some cases of ACD.15 The probable conclusion from these various studies is that in vivo cellular expression of cytokines is highly variable amidst a melange of inflammatory factors. The most consistent result from lesional studies has been the increased expression of IL-10, mirrored by clearly increased spontaneous production of IL-10 by AD monocytes in vitro.15,16 The discovery of increased IL-10 production provides a rational explanation for the paradox of
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the increased and decreased cellular immune responses in AD. The suppressive effect of IL-10 on Th1 cell proliferation and function is well accepted, and in vitro studies indicate that monocytes might cause the decreased IFN-γ production by T cells from patients with AD.17 The therapeutic efficacy of systemic IL-10 in psoriasis, a condition of decreased IL-10 expression levels that now appears to be at the opposite pole from AD,16 highlights the potentially important pathogenic role that monocyte factors such as IL-10 can play in chronic inflammatory disease. Dendritic cells Considerable interest in recent years has focused on the possible pathogenic role of Langerhans cells (LCs) in AD. Increased numbers of these cells are seen in chronic AD lesions18; Bruynzeel-Koomen et al19 later demonstrated that more of these cells carried cytophilic IgE antibodies. Those observations led to the demonstration of FcεRII (CD23) expression and to the demonstration of FcεRI high-affinity IgE receptors on LCs and monocytes from patients with AD.20 Studies have shown that lesional LCs are hyperstimulatory for autologous T cells21 and that aeroallergen-specific IgE can increase the antigen-presenting function of LCs in patients with AD.22 These findings suggest a possible mechanism by which IgE might contribute to the abnormal cellular immune and eczematous responses seen in AD. Eosinophils The consistent presence of eosinophils in AD lesions lay hidden until 1985, when Leiferman et al23 detected their presence, often in a degradative state, through the use of labeled antibodies against eosinophil-specific major basic protein (MBP). Eosinophil proteins such as MBP and eosinophil cationic protein (ECP) are toxic substances that could themselves create the inflammatory milieu that manifests clinically as AD. Studies showing increased MBP in skin biopsy specimens after positive food challenge reactions are a major source of support for the etiologic role of food allergy in eczematous AD lesions.24 In the past year, Beck et al25 have shown that persons with clinical allergic respiratory disease have a greater eosinophilic response to intradermal injections of the eosinophil-tactic cytokine RANTES. Recent studies have also indicated that the production of eotaxin, another protein chemotactic for eosinophils, is induced in IL-4-treated fibroblasts in vitro.26 These studies provide substantial evidence for the role of eosinophils as major effector cells in AD.
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PHARMACOPHYSIOLOGIC ABNORMALITIES Clinical observations of patients with AD have pointed to many physiologic and pharmacologic aberrations, including acral vasodilatation, positive cold-pressor test, white dermographism, and a peculiar delayed blanch response to intradermal acetylcholine and methacholine.27 Similarly, patients with reactive airways or asthma overreact to inhaled methacholine, a response widely used to diagnose susceptibility to asthma.28 Such observations moved Szentivanyi29 to suggest in 1968 that atopic patients behaved as though they had a “blockade” of β-adrenergic receptors, causing a cholinergic overbalance. He proposed that atopy is a disease of over-reactive pharmacologic reactivity. Immunologic reactions would be only one group along with infections, chemical, physical and psychic stimuli, which might trigger the pathologic hyper-reactivity. His work led to in vitro assessments of cyclic AMP (cAMP) responses in peripheral leukocytes, which showed deficient cAMP responses to β-adrenergic agents in AD leukocyte cell cultures.30 The clue that this defect was not limited to the β-adrenergic receptor was the finding that similarly deficient cAMP responses occurred with stimulation by other adenylyl cyclase agonists such as prostaglandin E2 and histamine.31 The defect must therefore be further down the stimulatory pathway. This revelation led to demonstration of increased cAMP hydrolysis by overly active phosphodiesterase (PDE) isoforms in atopic leukocytes.32,33
TOWARD A PATHOPHYSIOLOGIC PARADIGM These studies collectively provided a basis for unifying the immunologic and pharmacophysiologic defects that are so ubiquitous in AD leukocytes and in the clinical disease. Another key to our understanding of this wide-based regulatory dysfunction was the demonstration that atopy, including airway reactivity, eczema, and antigen-specific IgE reactivity, could be transferred by bone marrow transplantation.1 Thus abnormal expression of probably multiple, atopy-associated genes is carried by hematopoietic cells that, when they infiltrate skin and mucosal sites, react inappropriately to cause clinical disease. This information has led to the development of two pathophysiologic paradigms: one centered on fundamental abnormalities in cyclic nucleotide regulation of marrow-derived cells, and the other on the belief that allergenic overstimulation causes secondary immunologic and pharmacophysiologic abnormalities.
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cAMP PDE abnormalities In this hypothesis, the core deficit in atopy lies in genetically defined PDE isoforms that lead to inadequate cellular cAMP levels. Because cAMP normally causes negative modulation of immune and inflammatory responses, inflammatory cells fail to shut off normally. This hyperreactivity culminates in what we see in atopy—excess reactivity to irritants, infectious agents, and antigens that includes increased production of IL-4 and IgE, monocyte secretion of IL-10 and prostaglandin E2, and excessive release of histamine by mast cells and basophils.3 This more comprehensive paradigm explains the dominant nonimmunologic characteristics of AD such as hyperirritancy and reactive airway disease, even in those 20% of patients lacking allergic IgE reactivity.28,34 The allergy hypothesis This hypothesis holds that early (perhaps even in utero) antigenic exposures cause the genetically susceptible person to proliferate antigenically stimulated Th2-dominant T-cell clones, which elaborate IL-4, IL5, IL-6, IL-10, and IL-13 on re-exposure to the antigen. These factors, in turn, stimulate excessive IgE production by the B cell and a tendency to eosinophilrich inflammation. This creates a milieu for mast cellinitiated inflammation that, if repeated over a long period, can produce eczematous disease, asthma, and allergic rhinitis. According to this hypothesis, decreased cyclic nucleotide production by stimulated leukocytes represents a secondary effect of this immunologic stimulation, although it has not yet been possible to generate the specific atypical PDE isoforms by in vitro perturbations.
EXTENDING THEORIES TO THERAPY These theories represent classic “chicken and egg” conflicts; controversies will no doubt reign until the atopic diseases are defined at a molecular genetic level. In the meantime, we can still utilize the information that we have to seek therapeutically approachable targets. In fact, the two pathophysiologic paradigms of cAMP/PDE abnormalities and allergy have given rise over recent years to two novel therapeutic approaches to AD: PDE inhibition and immune intervention. PDE inhibition PDE inhibitors target the cyclic nucleotide abnormalities characteristic of AD (Fig 1). Drugs such as theophylline and other agents have been used for many years in the treatment of asthma. However, theophylline lacks sufficient potency to have much
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B A
Fig 1. A, Adenylyl cyclase stimulatory agents (eg, epinephrine, prostaglandin E2, histamine) bind their respective receptors to generate cAMP production, which in turn activates protein kinase A (PKA), inhibiting protein kinase C (PKC). B, This reduces mediator release and the other leukocyte functions shown here. PDE activity, which is increased in atopic leukocytes, causes increased release of a variety of mediators and cytokines. Each of these cell functions is reduced by PDE inhibitors.
effect in AD, and systemic treatment with newer, more potent PDE inhibitors has been associated with a high incidence of nausea and vomiting.35 Topical caffeine showed efficacy in one study, but the compound was weak and cosmetically unacceptable.36 Newer type IV PDE inhibitors have evolved through the years and are coming under increased research scrutiny for asthma and AD.37 Ro 20-1724 as a 1% cream was shown to be about as effective as 1% hydrocortisone cream, but the compound was not developed further. More recently, our group screened several compounds for in vitro potency and identified one (CP-80633) that is 3 logs more potent than theophylline.38 It provided rapid and persistent anti-inflammatory activity when applied as a 0.5% cream to AD lesions, with no adverse reactions.38 This drug is currently under development and other even more potent PDE inhibitors can be anticipated in coming years. Disease-modifying immune intervention Immunosuppressive agents have traditionally included steroids, azathioprine, and methotrexate. In this discussion, we will focus on the new, more selective drugs for immune intervention. These structurally distinct compounds all bind to unrelated cytosolic binding proteins, known as immunophilins,39,40 but have a common result: the formation of inhibitory complexes that block calcineurin phosphatase activity, which, in turn, inhibits initiation of cytokine transcription and activation of T cells (Fig 2). Drugs that act by this mechanism and are currently under varying stages of clinical development include oral cyclosporine and topical macrolactam
Fig 2. Cyclosporine and FK506 bind their respective phosphatase-binding sites (cyclophilin and FK-binding protein 12 [FKBP12]), blocking action of nuclear factor in activated T cells (NF-AT) and, in turn, inhibiting cytokine (eg, IL-4) gene activation.
agents, such as FK506, and the ascomycin derivative SDZ ASM 981. Oral cyclosporine has been explored during the past 10 years for the treatment of AD and psoriasis, and its efficacy supports the view that these diseases are characterized by T-cell activation. However, concern about systemic side effects, especially renal toxicity, has limited the use of this drug to all but the most severe and refractory patients. Attempts to administer cyclosporine topically in both AD and psoriasis have failed, presumably because of poor percutaneous penetration.41 Another calcineurin inhibitor used to prevent transplant rejection, FK506, is 10 to 100 times more
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potent than cyclosporine in inhibiting T-cell activation.40,42 Its topical application has been shown to be effective in animal models of inflammation as well as in short-term clinical trials in AD.42-44 FK506 ointment is absorbed passively through the skin, with only a small fraction of the drug entering the systemic circulation.45 Phase I data using 0.3% FK506 ointment indicate that systemic absorption of the drug is low and decreases as local inflammatory conditions improve. Furthermore, the drug does not appear to accumulate in the skin or in the systemic circulation after repeated topical administration.45 Although initial application site burning and itching still occur, no systemic side effects have been reported in short-term clinical trials, and additional trials of this promising agent are under way.46 The newest drugs for immune intervention are the inflammatory cytokine inhibitors derived from the macrolactam ascomycin. SDZ ASM 981 is the most advanced in development. When applied topically in preclinical models, SDZ ASM 981 proved to be as potent as the corticosteroid clobetasol, without its local side effects.47 In addition, SDZ ASM 981—in contrast to cyclosporine and FK506— showed only a low potential for systemic immunosuppression when administered orally.47 The clinical efficacy and safety of SDZ ASM 981 have been confirmed in short-term trials in patients with moderate AD.48 Twice-daily applications were well tolerated, with no systemic adverse reactions. Although localized burning and stinging, resembling reactions to topical FK506, occurred, there was no skin atrophy, such as often occurs after use of topical corticosteroids. Systemic exposure after topical administration was low, with blood concentrations of the drug after repeated applications in patients with AD proving similar to those following a single application in healthy volunteers.47,48 This promising preclinical and early clinical profile suggests that the topical macrolactam immunosuppressants may offer the potent activity of a topical corticosteroid, without local side effects, such as skin atrophy.49 Additional clinical investigations are ongoing. Long-term safety evaluations of both FK506 and SDZ ASM 981 will be important in defining the future of these much-needed drugs for treating patients with AD.
CONCLUSION Novel therapies, including PDE inhibitors and new drugs for disease-modifying immune-intervention out of the group of ascomycins and FK506, provide a revolutionary approach to treatment of AD, allowing us to sidestep controversies of pathogenesis and to focus on potent benefit to our patients.
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During 4 decades, we have been limited largely to oral and topical glucocorticosteroid drugs that conferred increased toxicity parallel to increased potency of new compounds. As the new macrolides and PDE inhibitors become available, we must recall the corticosteroid example and realize that adverse effects, especially with topical agents, may not be detected until the drugs have been used for a year or more. Barring major complications, however, the advent of new effective agents will provide alternatives to corticosteroid monotherapy that will allow cycles of two or more drug treatment regimens that can reduce the magnitude of steroid toxicity. This can be of great value, especially in allowing treatment of steroid-sensitive areas such as the face and neck, and caring safely for children.45 Steroid-sparing alternative regimens that have provided more effective rotational therapy for psoriasis in recent years would appear to be approaching reality for AD as well. REFERENCES 1. Agosti JM, Sprenger JD, Lum LG, Witherspoon RP, Fisher LD, Storb R, et al. Transfer of allergen-specific IgE-mediated hypersensitivity with allogeneic bone marrow transplantation. N Engl J Med 1988;319:1623-8. 2. Thepen T, Langeveld-Wildschut G, Bihari IC, Van Wichen DF, Van Reijsen FC, Mudde GC. Biphasic response against aeroallergen in atopic dermatitis showing a switch from an initial TH2 response to a TH1 response in situ: an immunocytochemical study. J Allergy Clin Immunol 1996;97:828-37. 3. Hanifin JM, Chan SC. Monocyte phosphodiesterase abnormalities and dysregulation of lymphocyte function in atopic dermatitis. J Invest Dermatol 1995;105(suppl):84S-88S. 4. Ohman S, Johansson SG. Immunoglobulins in atopic dermatitis. Acta Derm Venereol (Stockh) 1974;54:193. 5. Jones HE, Inouye JC, McGerity JL, Lewis CW. Atopic disease and serum immunoglobulin-E. Br J Dermatol 1975;92:17-25. 6. Peterson RD, Page AR, Good RA. Wheal and erythema allergy in patients with agammaglobulinemia. J Allergy 1966;33:406-11. 7. Hanifin JM, Schneider LC, Leung DYM, Ellis CN, Jaffe HS, Izu AE, et al. Recombinant interferon-gamma therapy for atopic dermatitis. J Am Acad Dermatol 1993;28:189-97. 8. Hanifin JM, Lobitz WC. Newer concepts of atopic dermatitis. Arch Dermatol 1977;113:663-70. 9. Elliott ST, Hanifin JM. Delayed cutaneous hypersensitivity and lymphocyte transformation: dissociation in atopic dermatitis. Arch Dermatol 1979;115:36-9. 10. Zachary CB, Allen MH, MacDonald DM. In situ quantification of T-lymphocyte subsets and Langerhans cells in the inflammatory infiltrate of atopic eczema. Br J Dermatol 1985;112:149-56. 11. Reinhold U, Wehrmann W, Kukel S, Kreysel HW. Recombinant interferon-γ in severe atopic dermatitis. Lancet 1990;1:1282. 12. Jujo KH, Renz J, Abe EW, Leung DY. Decreased interferongamma and increased interleukin 4 production in atopic dermatitis promotes IgE synthesis. J Allergy Clin Immunol 1992;90:323-31. 13. Chan SC, Li S-H, Hanifin JM. Increased interleukin 4 production by atopic mononuclear leukocytes correlates with increased cyclic AMP-PDE activity and is reversible by PDE inhibition. J Invest Dermatol 1993;100:681-4.
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14. Grewe M, Walther S, Gyufko K, Czech W, Schopf E, Krutmann J. Analysis of the cytokine pattern expressed in situ in inhalant allergen patch test reactions of atopic dermatitis patients. J Invest Dermatol 1995;105:407-10. 15. Ohmen JD, Hanifin JM, Nickoloff BJ, Rea TH, Wyzykowski R, Kim J. Overexpression of IL-10 in atopic dermatitis: contrasting cytokine patterns with delayed-type hypersensitivity reactions. J Immunol 1995;154:1956-63. 16. Asadullah K, Sterry W, Stephanek K, Jasulaitis D, Leupold M, Audring H. IL-10 is a key cytokine in psoriasis: proof of principle by IL-10 therapy: a new therapeutic approach. JClin Invest 1998;101:783-94. 17. Chan SC, Kim J-W, Henderson WR Jr, Hanifin JM. Altered prostaglandin E2 regulation of cytokine production in atopic dermatitis. J Immunol 1993;151:3345-52. 18. Uno H, Hanifin JM. Langerhans cells in acute and chronic epidermal lesions of atopic dermatitis, observed by L-Dopa histofluorescence, glycol methacrylate thin section, and electron microscopy. J Invest Dermatol 1980;75:52-60. 19. Bruynzeel-Koomen CA, van Wichen DF, Toonstra J, Berrens L, Bruynzeel PL. The presence of IgE molecules on epidermal Langerhans cells in patients with atopic dermatitis. Arch Dermatol Res 1986;278:199-205. 20. Bieber T, de la Salle C,Wollenberg A, Chizzonite R, Hakimi J, et al. Human Langerhans cells express the high-affinity receptor for immunoglobulin E. J Exp Med 1992;175:1285-90. 21. Taylor RS, Baadsgaard O, Hammerberg C, Cooper KD. Hyperstimulatory CD1a+CD1b+CD36+ Langerhans cells are responsible for increased autologous T lymphocyte reactivity to lesional epidermal cells of patients with atopic dermatitis. JImmunol 1991;147:3794-802. 22. Mudde GC,Van Reijsen FC, Boland GJ, De Gast GC, Bruijnkeel PL, Bruijnkeel-Koomen CA. Allergen presentation by epidermal Langerhans cells from patients with atopic dermatitis is mediated by IgE. Immunology 1990;69:335-41. 23. Leiferman KM, Ackerman SJ, Sampson HA, Haugen HS,Venencie PY, Gleich GJ. Dermal deposition of eosinophil-granule major basic protein in atopic dermatitis. N Engl J Med 1985;313:28285. 24. Ott NL, Gleich GJ, Peterson EA, Fujisawa T, Sur S, Leiferman KM. Assessment of eosinophil and neutrophil participation in atopic dermatitis: comparison with the IgE-mediated latephase reaction. J Allergy Clin Immunol 1994;94:120-8. 25. Beck LA, Dalke S, Leiferman KM, Bickel CA, Hamilton R, Rosen H. Cutaneous injection of RANTES causes eosinophil recruitment: comparison of nonallergic and allergic human subjects. J Immunol 1997;159:2962-72. 26. Mochizuki M, Bartels J, Mallet AI, Christophers E, Schroder JM. IL4 induces eotaxin: a possible mechanism of selective eosinophil recruitment in Helminth infection and atopy. JImmunol 1998;160:60-8. 27. Hanifin JM. Pharmacophysiology of atopic dermatitis. Clin Rev Allergy 1986;4:43-65. 28. Barker AF, Hirshman CA, D’Silva R, Hanifin JM. Airway responsiveness in atopic dermatitis. JAllergy Clin Immunol 1991;87: 780-3. 29. Szentivanyi A. The beta-adrenergic theory of the atopic abnormality in bronchial asthma. JAllergy 1968;42:203-32. 30. Parker CS, Eisen AZ. Altered cyclic-AMP metabolism in atopic eczema. Clin Res 1972;20:418. 31. Safko MJ, Chan SC, Cooper KD, Hanifin JM. Heterologous desensitization of leukocytes: a possible mechanism of beta adrenergic blockade in atopic dermatitis. J Allergy Clin Immunol 1981;68:218-25.
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32. Grewe SR, Chan SC, Hanifin JM. Elevated leukocyte cyclic AMPphosphodiesterase in atopic disease: a possible mechanism for cyclic AMP-agonist hyporesponsiveness. JAllergy Clin Immunol 1982;70:452-7. 33. Chan SC, Reifsnyder D, Beavo JA, Hanifin JM. Immunochemical characterization of the distinct monocyte cyclic AMP-phosphodiesterase from patients with atopic dermatitis. JAllergy Clin Immunol 1993;91:1179-88. 34. Nassif A, Chan SC, Storrs FJ, Hanifin JM. Abnormal skin irritancy in atopic dermatitis and in atopy without dermatitis. Arch Dermatol 1994;130:1402-7. 35. Torphy TJ, Undem BJ. Phosphodiesterase inhibitors: new opportunities for the treatment of asthma. Thorax 1991;46:512-23. 36. Kaplan RJ, Daman L, Rosenberg EW, Feigenbaum S. Topical use of caffeine with hydrocortisone in the treatment of atopic dermatitis. Arch Dermatol 1978;114:60-2. 37. Houslay MD, Sullivan M, Bolger GB. The multienzyme PDE4 cyclic adenosine monophosphate-specific phosphodiesterase family: intracellular targeting, regulation, and selective inhibition by compounds exerting anti-inflammatory and antidepressant actions. Adv Pharmacol 1998;44:225-342. 38. Hanifin JM, Chan SC, Cheng JB, Toffe SJ, Henderson WR Jr, Kirby DS, et al. Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis. J Invest Dermatol 1996;107:51-6. 39. Ho S, Clipstone N, Timmerman L, Northrop J, Graef I, Fiorentino D, et al. The mechanism of action of cyclosporin A and FK506. Clin Immunol Immunopathol 1996;80:S40-S45. 40. Bieber T. Topical tacrolimus (FK 506): a new milestone in the management of atopic dermatitis. J Allergy Clin Immunol 1998;102:555-7. 41. De Rie MA, Meinardi MHM, Dos J. Lack of efficacy of topical cyclosporin A in atopic dermatitis and allergic contact dermatitis. Acta Derm Venereol (Stockh) 1991;71:452-4. 42. Ruzicka T, Bieber T, Schöpf E, Rubins A, Dobozy A, Bos JD, et al (for the European Tacrolimus Multicenter Atopic Dermatitis Study Group). A short-term trial of tacrolimus ointment for atopic dermatitis. NEngl J Med 1997;337:816-21. 43. Aoyama H, Tabata N, Tanaka M, Vesugi Y, Tagami H. Successful treatment of resistant facial lesions of atopic dermatitis with 0.1% FK506 ointment. Br J Dermatol 1995;133:494-6. 44. Nakagawa H, Etoh T, Ishibashi Y, et al. Effects of tacrolimus (FK506) ointment for facial atopic dermatitis. Allergy 1995; 50:368. 45. Alaiti S, Kang S, Fiedler VC, et al.Tacrolimus (FK506) ointment for atopic dermatitis: a phase I study in adults and children. J Am Acad Dermatol 1998;38:69-76. 46. Boguniewicz M, Fiedler VC, Raimer S, Ellis CN, Spurlin DV, Fader D, et al. A randomized vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children. J Allergy Clin Immunol 1998;102:635-42. 47. Meingassner JG, Grassberger M, Fahrngruber H, Moore HD, Schuurman H, Stutz A. A novel anti-inflammatory drug, SDZ ASM 981, for the topical and oral treatment of skin diseases: in vivo pharmacology. Br J Dermatol 1997;137:568-76. 48. Van Leent EJ, Graber M, Thurston M, Wagenaar A, Spuls PI, Bos JD. Effectiveness of the ascomycin macrolactam SDZ ASM 981 in the topical treatment of atopic dermatitis. Arch Dermatol 1998;134:805-9. 49. Reitamo S, Rissanen J, Remitz A, Granlund H, Erkko P, Elg P, et al. Tacrolimus ointment does not affect collagen synthesis: results of a single-center randomized trial. J Invest Dermatol 1998; 111:396-8.