Clinical study of a patient with lupus vulgaris before and after injection of dialyzable transfer factor.

This report describes the clinical improvement and acquisition of tuberculin skin-test sensitivity by a tuberculin-negative, drug-resistant patient with lupus vulgaris after a single injection of dialyzable transfer factor (TFd) from a tuberculin-positive healthy donor. The patient's lymphocytes showed a slight response to tuberculin in the leukocyte migration inhibition test and in the lymphocyte transformation test before TFd injection. The acquisition of cellular immunity to tuberculin was demonstrated in vitro by enhanced tuberculin-induced blast transformation. A good correlation between skin test and in vitro tuberculin sensitivity and clinical improvement was seen during the three years that the patient was observed.     

In vitro studies in nickel allergy: diagnostic value of a dual parameter analysis

A comparison was made between the diagnostic value of assaying nickel-induced lymphocyte proliferation (lymphocyte transformation test, LTT) and migration inhibition factor (MIF) production in nickel contact sensitivity. Although lymphocyte proliferation was significantly increased in the group of patients with skin test reactivity to nickel, positive LTT were also frequently found in skin test-negative subjects: in 63% of subjects with and in 30% of subjects without a history of metal allergy. This would limit the value of the LTT as an in vitro correlate of skin test reactivity. However, in certain patients positive lymphocyte transformation may reveal nickel sensitization at a time of undetectable skin reactivity. Data obtained with the macrophage migration inhibition test (MMIT) showed a good correlation with nickel patch test reactions. Accurate determination of MIF became feasible by using cells from the human monocytoid cell line U937 as target cells in a microdroplet agarose assay. Using this MMIT, positive reactions occurred in 13% of the healthy controls and false-negative reactions were found in 26% of patients with positive skin test reactivity to nickel. As LTT and MMIT data appeared to be only weakly correlated in the individuals tested, a dual parameter analysis was performed. An excellent correlation [p = 1.8 (10(-8]] was found between skin test and in vitro reactivity for individuals with matching in vitro results (60% of all individuals tested). In those individuals with discordant in vitro data, skin testing will remain indispensable for diagnosing nickel allergy.     

MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF) IN GUINEA PIGS AND HUMANS WITH DELAYED HYPERSENSITIVITY

When lymph node cells from PPD-sensitive guinea pigs were incubated with PPD for 20–24 hours, they produced a soluble mediator which inhibited the migration of normal guinea pig peritoneal exudate cells (GP-PEC) out of capillary tubes. Also, human lymphocytes stimulated by antigen produced a soluble mediator which inhibited migration of normal GP-PEC and peripheral leukocytes. Guinea pig migration inhibitory factor (MIF) was eluted in the 34,000–67,000 molecular weight (MW) region of cultured supernatants. Human MIF was harvested from the 25,000 MW region of cultured supernatants from human lymphocytes fractionated on Sephadex G-100. Intradermal injection of the MIF into normal guinea pigs provoked reactions characterized by erythema and induration. The histologic response was found to be similar to that induced by antigen injection into sensitized animals. MIF from antigen stimulated lymphocytes may not have species specificity between guinea pig and human, although their molecular weights are different. No correlation was found between delayed skin reactivity induced by antigen in vivo and MIF production in vitro, and it is suggested that a substance inhibitory to MIF activity may be released in the lymphocyte culture.     

Transfer factor in the treatment of chronic mucocutaneous candidiasis: a controlled study

A controlled cross-over study with transfer factor was carried out on 7 patients suffering from chronic mucocutaneous candidiasis. Only one patient showed clinical improvement, which started during a period of pretreatment with 5-fluorocytosine given orally 14 days before the patient entered this trial. No conversion to a positive skin test with Candida antigen or PPD was demonstrated following TF in the 6 patients who were anergic to either of these antigens. Variations in the cell-mediated immune response as revealed by lymphocyte transformation were observed in most patients, especially when studied over a long period of time. However, no pronounced efficacy of TF vis-à-vis placebo in normalizing the cell-mediated immune response could be demonstrated in the 5 patients who completed the clinical trial. Systemic side effects were not observed.     

Acquired chronic candidiasis treated with transfer factor

A patient with acquired chronic oral and vaginal candidiasis resistant to topical and parenteral therapy was found to have impaired cell mediated immunity to Candida antigen and loss of skin test response to tuberculin (Mantoux). Treatment with Candida-active transfer factor produced clinical remission lasting 1 year and restitution of in vitro and in vivo immune parameters. Relapse occurred while receiving a second lot of transfer factor from the same donor. Subsequent treatment with levamisole was associated with onset of agranulocytosis.     

Darier's disease: an immunologic study.

Darier's disease is frequently complicated by bacterial skin infections and occasionally by Kaposi's varicelliform eruption. Postulating that defective host immunologic competence might explain these infections, humoral and cell-mediated immunity (CMI) were evaluated in four patients. Humoral immunity was normal as demonstrated by quantitative immunoglobulins, isohemagglutinins, direct skin immunofluorescence, and B-cell counts. The CMI was evaluated by standard delayed type hypersensitivity skin tests, T-cell counts, lymphocyte transformation assays, macrophage inhibition factor (MIF) assays, and skin windows. Blunted lymphocyte blastogenesis, MIF, and skin window response indicated depressed CMI. Polymorphonuclear leukocyte chemotaxis and phagocytosis were normal.     

In vitro release of interferon-gamma and macrophage migration inhibition factor in drug-induced urticaria and angioedema

T-cells are involved in the pathogenesis of cutaneous drug reactions. T-cell phenotype and cytokine release pattern in rivo and in vitro might correlate with the type of immune response involved in cutaneous drug reactions. In vitro release of interferon-gamma and macrophage migration inhibition factor (MIF) from peripheral blood lymphocytes, following in vitro challenge with the suspected unmodified drugs, was studied in 12 patients with drug-induced urticaria and/or angioedema and in two group-matched controls. The occurrence of positive interferon-gamma and MIF responses was significantly higher in patients with drug-induced urticaria and/or angioedema than in controls. The sensitivity and specificity of the interferon-gamma test (50% and 92%, respectively) were similar to that of the MIF test (58% and 96%, respectively). Percentage agreement between both tests was 80.9 (kappa = 0.76). In vitro release of interferon-gamma and MIF in drug-induced urticaria and/or angioedema suggests a drug-specific immune response, and may implicate the drug as a possible inducer of the reaction.     

Ichthyosiform sarcoidosis

A 31-year-old black woman had acquired ichthyosis. Histologic examination of her skin revealed a sarcoidal reaction in the dermis. The diagnosis of sarcoidosis was supported by negative tuberculin (intermediate strength purified protein derivative) and Candida albicans extract intradermal skin tests; by a positive Kveim test; and by roentgenographic evidence of bilateral hilar adenopathy, paratracheal node enlargement, and diffuse pulmonary parenchymal changes. Sarcoidosis must be considered when acquired ichthyosis develops in a patient.     

Macrophage migration inhibitory factor is essential for eosinophil recruitment in allergen-induced skin inflammation

Macrophage migration inhibitory factor (MIF) is a pluripotent cytokine that has an essential role in the pathophysiology of experimental allergic inflammation. Recent findings suggest that MIF is involved in several allergic disorders, including atopic dermatitis (AD). In this study, the role of MIF in allergic skin inflammation was examined using a murine model of AD elicited by epicutaneous sensitization with ovalbumin (OVA). We observed the number of skin-infiltrating eosinophils to significantly increase in OVA-sensitized MIF transgenic (Tg) mice compared with their wild-type (WT) littermates. On the other hand, eosinophils were virtually absent from the skin of MIF knockout (KO) mice and failed to infiltrate their skin after repeated epicutaneous sensitization with OVA. The mRNA expression levels of eotaxin and IL-5 were significantly increased in OVA-sensitized skin sites of MIF Tg mice, but were significantly decreased in MIF KO mice in comparison with the levels in WT littermates. Eotaxin expression was induced by IL-4 stimulation in fibroblasts in MIF Tg mice, but not in MIF KO mice. These findings indicate that MIF can induce eosinophil accumulation in the skin. Therefore, the targeted inhibition of MIF might be a promising new therapeutic strategy for allergic skin diseases.     

Lymphocyte transformation, IgE and T-cells in eczema vaccinatum treated with transfer factor. A case report.

Transfer factor (TF) was given to intensify the cell-mediated immune reactions in an atopic patient with generalized vaccinia. The patient showed marked reactivity of peripheral blood lymphocytes to stimulation with phytohaemagglutinin and pokeweed mitogen, but also in nonstimulated cultures. However, later tests with mitogen stimulation of lymphocytes indicated a defective cellular defence mechanism. The addition of autologous plasma to lymphocyte cultures depressed the reactivity of PHA-stimulation considerably. Initially, the patient also showed a normal T-lymphocyte count in peripheral blood, but six months after her vaccinia, extremely high serum IgE levels and a decreased percentage of T-lymphocytes was observed. Although an evaluation of the clinical effect of transfer factor injection is difficult, it should be noted that the patient's temperature immediately fell to normal, and her general health improved following treatment.     

An AIDS patient with atopic dermatitis-like eruption responsive to systemic anti-fungal treatment.

Patients with the acquired immunodeficiency syndrome (AIDS) often develop unusual skin complications. We describe a case of a 58-year-old man with AIDS who had a history of multiple transfusions with anti-hemophilic factor A. He developed papulovesicular and lichenified skin lesions on his head, face, neck and the extensor aspects of his extremities accompanied by severe pruritus. Atopic dermatitis was suspected; however, intensive treatment with a potent topical corticosteroid and a systemic antihistamine failed. In addition to the decreased subset of CD4-positive lymphocytes characteristic of AIDS, this patient showed an elevated level of serum IgE particularly specific for Candida albicans, probably because he had a chronic candidial infection of the digestive tract. Oral administration of anti-fungal agents Diflucan and Fungizone produced almost complete relief from the atopic dermatitis-like skin disease within 2 weeks.     

糖皮质激素治疗SLE不反应的分子机制

SLE治疗过程中,糖皮质激素的治疗不反应是目前临床遇到的棘手问题.近年来的研究发现,SLE外周血活化淋巴细胞膜表面P-糖蛋白的高表达,促使进入淋巴细胞内的糖皮质激素被泵出或巨噬细胞移动抑制因子自分泌增加,拮抗激素的抗炎活性,共同参与诱导SLE患者对激素治疗的不反应.抑制或下调淋巴细胞P-糖蛋白活性和巨噬细胞移动抑制因子的表达,有可能促使临床逆转对激素治疗的抵抗.     

Failure of transfer factor therapy in atopic dermatitis.

A controlled clinical study was conducted on 6 patients with atopic dermatitis to assess the efficacy of transfer factor. After the code was broken the 3 patients treated with placebo preparation were treated with transfer factor for a further period of 10 weeks. No definite therapeutic effects could be demonstrated. The immunological in vivo and in vitro tests failed to reveal any effects except for a change to positive in the tuberculin skin test in those patients who had previously been skin test negative. The treatment had to be discontinued in one patient due to a suspected allergic reaction against transfer factor.     

A chronic contact eczema impedes migration of antigen-presenting cells in alopecia areata

Long-lasting allergen treatment is the most efficient therapy in alopecia areata (AA). The underlying mechanism is unknown. We here asked whether treatment with a contact sensitizer influences leukocyte migration such that dendritic cell (DC) migration or the recruitment of activated T-cells towards the skin become hampered. Allergen treatment of AA mice was not accompanied by a decrease in skin-infiltrating leukocytes or draining lymph node cells (LNC). However, the distribution of leukocyte subsets was changed with a dominance of monocytes in the skin and a reduced percentage of DCs in draining nodes. Chemokine and chemokine receptor expression in skin and draining nodes was strikingly increased and LNC from untreated and allergen-treated AA mice showed high migratory activity in vitro and readily homed in draining nodes and skin after intravenous injection. However, FITC labelling of the skin and subcutaneous transfer of dye-labelled DC revealed that allergen treatment created a chemokine milieu severely hampering DC migration from the skin towards the draining node. An allergic eczema-induced reduction in DC migration and antigen transfer could well contribute to insufficient T-cell activation and the recovery of hair follicle in AA and possibly be of relevance for other skin-related autoimmune diseases.     

Cell-mediated immunity in vitro in atopic dermatitis.

The function of T cells in atopic dermatitis was studied by leukocyte migration agarose and lymphocyte transformation tests. We found that phytohemagglutinin (PHA)- and PPD-induced release of leukocyte migration inhibition factor (LIF) from lymphocytes is significantly decreased (P less than .001) in patients with atopic dermatitis as compared with healthy controls. Blastogenic response of lymphocytes induced by PPD was also decreased in atopic patients as compared with controls (P less than .01). No differences were found in spontaneous blastogenesis or in blastogenic response of lymphocytes in vitro to PHA, concanavalin A (ConA), or streptokinase-streptodornase (SK-SD) between patients with atopic dermatitis and controls.     

Pityriasis rosea and ketotifen

A 4-year-old female patient who developed a skin eruption similar to pityriasis rosea after treatment with ketotifen (Zaditen) is presented. The relationship between ketotifen and the eruption has been based on circumstantial evidence and confirmed by the positive results of the MIF test and the rat mast cell degranulation test.     

A study on the clinical application of a direct leukocyte migration test in chromium contact allergy

A capillary tube leukocyte migration inhibition assay has been adopted as an in vitro method for the demonstration of chromium hypersensitivity in twenty-two subjects with clinically proven or suspected chromium allergy. Two complexes of trivalent chromium and human serum albumin, exerting different migration inhibitory effects, have been prepared and used as the antigen. In the presence of the chromium-albumin complex with strong inhibitory activity, sensitivity to chromium was demonstrated independent of the clinical condition of the skin in all the patch test positive subjects. An additional positive response to the second chromium-albumin complex was observed only in those patients who were clinically in a state of exacerbation of an allergic contact dermatitis in which chromium allergy was an active causative factor. The results were not influenced by skin allergic reactivity to compounds other than chromium and the method was found to be of practical clinical value for diagnosing chromium allergy.     

Lymphocyte responsiveness to urinary glycosaminoglycan in systemic scleroderma.

From the urine of patients with systemic scleroderma, we previously isolated a glycosaminoglycan, which could induce a scleroderma-like change in the skin of mouse. In the present work, the cell-mediated response to urinary glycosaminoglycans was examined by lymphocyte transformation test. The specific response was observed in lymphocytes of patients with scleroderma, when the above scleroderma-inducing glycosaminoglycan was added. By contrast, lymphocytes of patients with SLE or dermatomyositis and of normal persons hardly showed a response to this glycosaminoglycan. On the other hand, the glycosaminoglycans from normal urine could not stimulate lymphocytes of patients with scleroderma or healthy persons.     

Reactivity of lymphocytes from patients with syphilis towards T. pallidum antigen in the leucocyte migration and lymphocyte transformation tests.

The reactivity of lymphocytes to Treponema pallidum antigen was studied before and after treatment in nine patients with early syphilis using a leucocyte migration test and a lymphocyte transformation test. Lymphocyte reactivity was also investigated in six patients treated for syphilis within the last 4 years, and in five untreated patients with a positive result to the T. pallidum immobilization test, but negative results to other serum tests for syphilis antibodies and without any known exposure to risk of infection by syphilis. Ten seronegative patients with different dermatological disorders served as a control group. A significant increase in lymphocyte reactivity to T. pallidum antigen was recorded in both tests in vitro after treatment. There was no difference in lymphocyte reactivity to T. pallidum antigen between the other patients studied and the control group. In early syphilis the spontaneous migration was found to be inhibited before treatment. Tuberculin skin tests were also performed and found to be suppressed in patients with primary and secondary syphilis. No difference in phytohaemagglutinin response was found between any of the groups. Plasma from patients with primary and secondary syphilis was found to change the in vitro reactivity of normal lymphocytes when stimulated with different mitogens.     

Experimental bullous pemphigoid in guinea pigs: the role of pemphigoid antibodies, complement, and migrating cells

Dermal-epidermal separation (DES) could be produced in vivo, 6 h after the injection of sera taken from patients with bullous pemphigoid into the dorsal skin of Hartley guinea pigs. DES did not occur when antihuman IgG rabbit serum was injected prior to the injection of the sera taken from patients with bullous pemphigoid. When IgG fraction from the patient's sera was injected, DES was also observed. Histologic findings in the skin specimens in vivo with concentrated sera or IgG fraction have shown DES, some cell infiltrations of neutrophils, eosinophils, and some lymphocytes similar to the skin lesions of bullous pemphigoid patients. Various reagents, such as colchicine, cytochalasin B, EDTA, and steroid were injected prior to the IgG fraction injection. DES and the migration of polymorphonuclear (PMN) leukocytes were inhibited by the preinjection of these reagents. These observations suggest that the migration of PMN leukocytes was necessary for the formation of DES. When IgG fraction was injected into C3-inactivated guinea pigs with cobra venom factor, DES was inhibited, whereas DES was not completely inhibited when IgG fraction was injected into C4-deficient guinea pigs. These results suggested that an alternative pathway may be necessary for DES.