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Allergic-like reactions to chemical components of foods and medicines may be common. The prevalence of idiosyncratic reactions to aspirin, salicylate, metabisulfite and tartrazine is not known. We used a tertiary referral clinic population to estimate safe exposure doses for epidemiological studies. A 15% decrease in the amount of air expired in one second was defined a positive response. The median effective molar doses of the agents were remarkably similar: metabisulfite 0.19 mM, 34.4 mg [95% confidence interval (CI) 0.14, 0.27 mM]; tartrazine 0.10 M, 55.0 mg (95% CI 0.05, 0.21 mM); aspirin 0.09 mM, 16.5 mg (95% CI 0.04, 0.19 mM); and salicylate 0.11 mM, 15.3 mg (95% CI 0.05, 0.27 mM). Doses to which the most sensitive (5%) and practically all (95%) susceptible persons might respectively respond are: metabisulfite 4.6 mg, 255.8 mg; tartrazine 3.4 mg, 885.6 mg; aspirin 0.8 mg, 332.3 mg; and salicylate 2.6 mg, 89.9 mg. Doses within these ranges can be used in epidemiological studies.

The impact of pollen on the respiratory mucosa was modeled by studying the process by which solutes are eluted from pollen grains. Rye grass (Lolium perenne), short ragweed (Ambrosia artemisiifolia), and white oak (Quercus alba) pollens were packed between glass wool plugs in small columns. Water was pumped through the columns and the eluate solute yield was determined by measurement of the dry solute weight. Solute separation was rapid, and concentrations and osmolalities of the eluate decreased exponentially. Theoretical initial solute concentrations were 179 g/l for rye grass, 55 g/l for short ragweed and 349 g/l for oak pollen eluates. Theoretical initial osmolarities of the same eluates were 321 mOsm/kg for rye grass, 196 mOsm/kg for ragweed and 424 mOsm/kg for oak pollen. Sequential separation of allergens (Lol p I, Amb a I, Amb a V), enzymes and proteins was demonstrated by specific assays. These observations suggest that the complex stimulus produced immediately after pollen grain hydration at the respiratory mucosal fluid interface is much more intense than previously envisioned. Sequential separation of pollen components has important implications for the production of improved allergenic extracts.

Delayed hypersensitivity skin tests with mycelium-derived (coccidioidin) or spherule-derived (spherulin) antigens (or both) can be used to identify patients who have been sensitized to the dimorphic fungus Coccidioides immitis. Prior studies suggest that coccidioidin and spherulin skin test antigens detect comparable numbers of reactors among exposed subjects. Studies in subjects residing in areas outside the United States where C. immitis is not endemic suggest that both antigens are specific for the fungus. The specificity and reactivity of coccidioidin and spherulin have not been compared in nonendemic regions of the United States in which the skin test antigens and an appropriate travel or exposure history are used to identify patients with possible C. immitis infection. A review of delayed cutaneous reactions to coccidioidin in 6,375 patients tested between 1970 and 1979 in the southeastern United States revealed 958 (15.0%) and 234 (5.7%) positive reactions (greater than or equal to 5 mm), respectively, at 24 and 48 h. Subsequent tests with spherulin in 2,775 patients tested in 1980 and 1981 revealed 866 (31.2%) and 288 (10.3%) positive reactions, respectively, at 24 and 48 h. False-positive immediate hypersensitivity reactions contributed to the large number of spherulin reactors at 24 h. Differences among the patients sampled, work exposure, and travel history were excluded as causes of this surprising and highly significant (P less than or equal to 0.0001) difference in the 48-h delayed cutaneous reaction. These observations suggest two possibilities: (i) spherulin is less specific than coccidioidin, or (ii) a surprising prevalence of C. immitis sensitization exists among patients in nonendemic regions of the United States.

A quantitative assessment of the long-term prognostic value and clinical usefulness of recall antigen reactions in patients with malignant melanoma is not available. The authors evaluated longitudinal observations of survival made in 846 patients over a 12-year period. Each patient was initially studied with Mantoux-type recall antigen skin tests. The patients were categorized with respect to the following: high (greater than 5 mm) or low (less than or equal to 5 mm) averaged skin test reaction diameters at 48 hr; Clark level; tumor stage (I = localized tumor, II = local extension and/or region lymph node metastasis, III = systemic metastasis); ulceration; site of primary; histologic type; age; and sex. The percentage of high reactors in Stages I, II, and III were 44.3%, 37.4%, and 25%, respectively. Survival was evaluated with the Cox-Mantell hazard function model and the Cox regression model. The significant (chi-squared; probability) risk factors detected were tumor stage (94.58; less than or equal to 0.0001), Clark level (19.37; less than or equal to 0.0001), sex (16.97; less than or equal to 0.0001), and skin test reactivity (7.48; less than or equal to 0.0062). A significant relationship also was detected between skin test reactor status and the tumor stage (p less than or equal to 0.0330). When evaluated within each stage of disease, skin test reactivity predicted survival only in Stage II patients (p less than or equal to 0.0080). Five-year survival estimates among Stage II patients were 58% among high reactors and 38% among low reactors.(ABSTRACT TRUNCATED AT 250 WORDS)

An extensive Phase I evaluation of human lymphoblastoid interferon has been completed which, in addition to describing its clinical and pharmacological effects, emphasized a broad-scale evaluation of the immune response as a function of interferon dosage. Dose-limiting toxicity was generally due to constitutional symptoms which are remarkably similar to those produced by influenza, although transient peripheral and central neurotoxicity (including deterioration in cognitive and behavioral functions) is observed at higher doses. It is difficult to establish "clean" dose-response effects except for fever and bone marrow suppression, neither of which is a major dose limitation. Enhancement of the immune system was limited to natural killer cells which had a complex dose-response relationship, whereby low interferon concentrations were less stimulatory (than were high doses) following a single dose but gave more sustained stimulation over a 5-week course of 3 times per week i.m. administration. The effects on various measures of monocyte function and of nonspecific immunity (hypersensitivity, immunoglobulins, complement) were negative. We suspect that in practice it may be difficult to exploit the narrow dosage window of immunostimulation, but it is important to note that the nontoxic lower doses were more stimulatory than were the very high doses which are being used in numerous clinical trials.

Until recently, the Waorani Indians of Ecuador's Amazon headwaters maintained a fierce resistance to all intruders into their territory, and as a result of their actions and reputations a population of 600 people controlled a very large territory (about 8,000 square miles). The isolation of the Waorani has resulted in a large linguistic and genetic distance from their neighbors. Our survey of red cell enzymes, immunoglobulin allotypes, and dermatoglyphics demonstrates that the Waorani are a highly inbred and homogeneous population. Of 18 red cell enzymes studied, the Waorani have a limited polymorphism for only 6. Only two Gm haplotypes (Gm1,2,17,21, Gm1,17,21) were found and 60% of those tested were homozygous for the Gm1,17,21 haplotype. All individuals were A2m (1) and 95% of these were homozygous. The Waorani's dermatoglyphic traits fell within the wide range found among other South American Indians with close affinity to the Ecuadorian Jivaro group. Despite the limitations of these genetic systems, they demonstrate that the Waorani share limited genetic traits with the neighboring Jivaro Indians and are isolated from other tribal populations in South America.

The survival over 18 months of 29 nursing home residents was compared with results of cutaneous testing of cell-mediated immunity at the start of the period of observation. Eight antigens were used to evaluate immunity by intradermal injection of each antigen and measurement of the areas of induration at 48 and 72 hours. A difference in responses was seen between the survivors and those who died, although this difference was statistically significant at 72 hours only. As expected, survivors had more (3.1, compared with 1.47) and larger (8.6 mm, compared with 3.2 mm) reactions at 72 hours than those who died.

Studies in human families and in surviving older persons suggest that the immune system may have an important role in the control of the survival. Immune response (Ir) genes to infectious agents can be detected in human families.

The effect of polyethylene glycol on the light scattering properties of immune complexes prepared in vitro was examined. Immune complexes were prepared in the zone of antigen excess from purified rabbit anti-ovalbumin and ovalbumin at 2-32 times (X) the equivalence ratio. Immune complex concentration was determined by analytical ultracentrifugation. Immune complexes were then incubated for 1 h in solutions containing 0, 1, 2, 3 and 4% polyethylene glycol (PEG), and examined in a laser nephelometer. The effect of PEG on light scattering (%RLS) was different for each immune complex combining ratio, although for each immune complex combining ratio, there was a linear relationship between the light scattered and immune complex concentration. To evaluate the effect of serum proteins on the light scattered by the immune complexes, immune complexes made at 4X and 16X the equivalence ratio were placed in serum and the sera containing these immune complexes were examined in the nephelometer. The ratio of the %RLS of the immune complexes in serum to the sum of the %RLS of the same immune complexes in saline plus the %RLS of serum alone was determined. This ratio varied systematically with changes in combining ratio and PEG concentration, as well as the concentration of the immune complexes themselves. Depending on the combination of these 3 factors, serum could increase, decrease or have no effect on the quantity of light scattered by the immune complexes. Discrimination between serum alone and serum containing immune complexes was best in 3% PEG.

Cutaneous reactions to allergens exhibit a sigmoid dose-response relationship. Available methods for evaluating the allergen skin-test response do not adequately account for the sigmoid curve. Methodologic factors handicap quantitative studies of allergens based on skin-test reactivity. This problem was evaluated with a pharmacologic agonist that mimics cutaneous reactivity. Epicutaneous tests with appropriate concentrations of methacholine were used to provoke flare responses in 84 healthy subjects. A novel hyperbolic tangent model of the sigmoid dose-response curve was used to estimate responsiveness (R) as the midpoint of the sigmoid curve. Sensitivity (C) was estimated as the agonist concentration yielding a flare response equivalent to R. Estimates of sensitivity were independent of estimates of responsiveness (r=-0.0565, p=0.6642). The geometric mean methacholine sensitivity among health subjects was 287 mM/L, and average methacholine responsiveness was 4.9 mm. The mathematic model used in these studies fitted observations surprisingly well (X2(84)=37.044, p greater than 0.95). Differences in methacholine sensitivity and responsiveness related to race, sex, and allergic and/or vasomotor tendencies were detected but were subtle and did not account for a significant portion of the variation among healthy subjects. This model may provide a useful method for quantifying cutaneous immediate hypersensitivity reactions in patients.

The kinetics, quantitative yield, and sequence of solute release during the extraction of allergenic substances from short ragweed (Ambrosia artemisiifolia) pollen were compared with a conventional batch-type method and the novel technique of pollen grain column chromatography. With the batch method, 14.6 +/- 1.7 mg of pollen solutes were eluted per 100 mg of dried defatted pollen in 1 minute; the 24-hour solute yield was 27.4 +/- 2.7 mg. With the column method, 3.7 +/- 1.3 mg of pollen solutes were eluted in 1 minute; the 24-hour solute yield was 29.3 +/- 2.1 mg. The kinetics of solute release with the column method were modeled as the simultaneous first-order elution of ragweed-pollen solutes into three hypothetical compartments. The theoretical initial solute concentration was 50 gm/L. The isoelectric focusing patterns, optical properties, distributions of enzymes, Ra5, and antigen E activities were consistent with the sequential separation of ragweed-pollen solutes and the three compartment model. Enzyme activities were eluted either maximally in the first minute (phosphatases and N-acetyl-beta-glucaminidase) or delayed until 10 minutes (leucine aminopeptidase). Ra5 was eluted rapidly, whereas antigen E was eluted during a more prolonged period. Pollen grain chromatography provides a simple, reproducible method for studying pollen solute release.

Serum samples were drawn from 14 healthy volunteers after an overnight fast and again after a meal. Each sample was divided into two aliquots. One aliquot was centrifuged at 20,000 rpm for 20 min, and a portion from the middle of the tube was removed by puncturing the tube's side. All samples were then added to cuvettes containing 0.14 M NaCl alone or 1, 2, 3, or 4% polyethylene glycol in 0.15 M KCl. The light scattering of each tube was measured. The centrifuged samples scattered 58% less light than the uncentrifuged controls. The range of values obtained with the centrifuged samples was also smaller as reflected in the standard deviation of the means obtained at each polyethylene glycol concentration. The coefficient of variation for replicate samples ranged from 0 to 16.6% (mean 5.8%), even when samples were processed differently. Storage at -70 degrees C significantly increased light scattering compared to baseline values. Serum samples were drawn from 44 patients with diseases that have been associated with immune complexes. Nephelometry selectively identified some groups of patients as abnormal. We conclude that preparative ultracentrifugation removes much of the background light scattering of serum samples, including that due to lipid, under conditions that do not sediment out immune complexes. Because it measures a physical property of immune complexes, this assay may provide information that is not available from biological receptor-based assays.

We performed a double-blind crossover trial of challenges with 30 mg of aspartame per kilogram of body weight or placebo in 40 subjects who reported having headaches repeatedly after consuming products containing aspartame. The incidence rate of headache after aspartame (35 percent) was not significantly different from that after placebo (45 percent) (P less than 0.50). No serious reactions were observed, and the incidence of symptoms other than headache following aspartame was also equivalent to that after placebo. No treatment-related effects were detected in vital signs, blood pressure, or plasma concentrations of cortisol, insulin, glucagon, histamine, epinephrine, or norepinephrine. Most of the subjects were well educated and overweight and had a family or personal history of allergic reactions. The subjects who had headaches had lower plasma concentrations of norepinephrine (P less than 0.0002) and epinephrine (P less than 0.02) just before the development of headache. We conclude that in this population, aspartame is no more likely to produce headache than placebo.

The flare reactions produced by epicutaneous tests with 68 undiluted allergenic pollen extracts were measured in 550 allergic patients. Skin test reactions greater than or equal to 2, greater than or equal to 5, greater than or equal to 10, greater than or equal to 20, and greater than or equal to 30 mm in diameter, respectively, were detected in approximately 67%, 22%, 10%, 3%, and 1% of the 34,700 skin tests. With the Kolmogorov-Smirnov difference test, the cumulative frequency of reaction diameters and loge-transformed diameters of all reactions and reactions to individual allergenic extracts differed significantly (p less than or equal to 0.01) from a normal distribution. The ability to identify specific differences between reactions to closely related pollen extracts was evaluated. Specific reactions could be reliably identified with greater than or equal to 10 mm diameter flares. This arbitrary conservative threshold was used to estimate the relative prevalence of positive reactions to each allergenic extract. Seven allergenic extracts elicited the first quartile of all positive reactions. Thirteen, 18, and 30 allergenic extracts, respectively, were needed to elicit the second, third, and fourth quartiles of all positive reactions. Reactions to amphiphilous, as well as anemophilous, pollens were detected. Skin test reactions to grasses were more prevalent than reactions to weeds and trees. The most informative allergenic extracts for the detection of patients who exhibited a positive reaction to any extract were from red fescue-grass pollens, mesquite, short ragweed, red clover, and timothy-grass pollens.

Three generations of a family were affected by hematologic malignancies: the proband had hairy cell leukemia, his brother chronic lymphocytic leukemia, his nephew cutaneous and central nervous system lymphoma, and his father chronic granulocytic leukemia. There was no clinical evidence for immune deficiency in 17 unaffected family members. Most family members had normal serum immunoglobulins and peripheral B-cells, but some had decreased T cells. Lymphocyte responses to phytohemagglutinin and concanavalin A were markedly reduced, while pokeweed mitogen responses were essentially normal. Delayed hypersensitivity responses determined by response to a 23-antigen skin test panel were markedly diminished, as were viral antibody titers. The decreased immune function in these family members suggests a role for the immune system in the emergence of hairy cell leukemia and other lymphoid malignancies, though further follow-up will be needed to see if other family members develop malignancies.

Yeast phase Candida albicans (ATCC No. 10231) was grown in a nonantigenic medium, harvested and lyophilized. Ammonium sulfate fractions of an aqueous extract of the lyophilized cells were evaluated and the fraction yielding the highest specific delayed cutaneous reactivity in sensitized guinea-pigs was used to prepare a C. albicans skin test antigen (CASTA). The safety of the antigen was evaluated by measuring immediate and delayed (0.25, 6, 24, 48 and 72 h) cutaneous reactions in atopic and nonatopic human subjects. The outcome of three repetitive monthly Mantoux skin tests with 0.01-1 microgram antigen doses was used to test for booster effects in 14 subjects and to estimate a safe initial test antigen dose. The utility of a single skin test as a measure of cell-mediated immunity was evaluated in 40 healthy subjects. Reactor rates (greater than or equal to 2 mm, 48 h) of 40% and 85% were detected, respectively, with doses of 0.0316 and 1 microgram. Using a skin test reaction diameter greater than or equal to 5 mm at 48 h, the reactor rate was 50% for the 1-microgram dose. The only adverse reaction (45 mm, 0.25 h) was detected with the 1-microgram dose in an atopic subject who also exhibited exquisite scratch test reaginic hypersensitivity to C. albicans allergen. The prevalence of other adverse reactions to this antigen compared favorably with that to other antigens used for recall antigen testing. These studies suggest the 1-microgram CASTA dose can be used for effective, safe recall antigen skin tests.

The Waorani Indians of eastern Ecuador have the highest blood concentration of IgE reported in a human population. Evidence obtained by medical history, physical examination, and immediate hypersensitivity skin tests suggests that pollen allergy and other atopic diseases are rare among the Waorani. A similar association between parasite-induced hyperimmunoglobulinemia-E and a low prevalence of conventional atopic disease has been reported in numerous other tropical populations. Saturation of mast cell IgE receptors with antibodies directed to the parasite and/or other antigens and competitive inhibition of passive binding of pollen allergen-specific IgE is one hypothetical cause of this association. We have tested this interesting conjecture by passively sensitizing the skin of Waorani Indians with serum containing pollen allergen-specific IgE antibodies. Waorani Indians with hyperimmunoglobulinemia-E can be adoptively sensitized with human ragweed or rye grass hyperimmune IgE antisera. This suggests that the cutaneous mast cells of healthy Waorani have active IgE receptors. The high circulating plasma concentrations of IgE in the Waorani do not prevent adoptive cutaneous sensitization with pollen-specific IgE antibodies.

The effectiveness of 60 mg b.i.d. of a novel antihistamine, terfenadine, was compared with an active control, 4 mg t.i.d. of chlorpheniramine, and placebo in 560 patients with seasonal allergic rhinitis. In contrast to the gradual decrease in seasonal symptoms observed over a 7 day period of study in placebo-treated patients, both antihistamines produced a prompt significant decrease in sneezing and rhinorrhea, and a gradual decrease in nasopharyngeal pruritus. Terfenadine-related sedation did not differ from that produced by the placebo and was less than the sedation produced by the active control.

Cutaneous responses to tuberculin and control antigens were measured in 24 HLA-B7 and 39 non-B7 patients before and 5-44 (average 10.5) weeks after BCG immunotherapy for malignant melanoma. Delayed tuberculin hypersensitivity increased after immunotherapy (p less than or equal 0.0001). The averaged area of induration (48 h) detected in HLA-B7 patients was half the area of induration of non-B7 patients before (p less than or equal to 0.0184) and after (p less than or equal to 0.0007) BCG treatment. Cutaneous anaphylactic hypersensitivity (0.25 h) responses to 19 of 22 antigens were significantly smaller (p less than 0.05) in HLA-B7 patients after BCG immunotherapy (p less than or equal to 0.0001). HLA-B7 patients had specific delayed cutaneous hyporesponsiveness to tuberculin and nonspecific cutaneous anaphylactic hyporesponsiveness after BCG immunotherapy.

We evaluated the incidence of allergic and vasomotor symptoms, serum IgE concentrations, and the cutaneous responses to allergens and/or methacholine in 229 Waorani Indians residing at 300 m altitude near the headwaters of the Amazon River, 39 Tibetans residing at 4000 m in the Himalayas, and 84 healthy subjects residing at 150 m in the piedmont region of North Carolina. The Waorani Indians had a high level of intestinal parasitism, an intermediate level of parasitism occurs in Tibetans, and parasitism is rare in the control population. One Waorani Indian (less than 1%), six Tibetans (15%), and 59 North Carolina subjects (88%) had a past history of allergic or vasomotor symptoms. The prevalence of positive epicutaneous allergen skin tests among the Waorani was 40 in 2910 tests and was significantly less (chi-squared = 184.5; p less than or equal to 0.0001) than the 151 in 1344 incidence in the North Carolina subjects. Large highly significant differences (p less than or equal to 0.0001) were detected between the geometric mean IgE concentrations (international unit per milliliter) and methacholine-induced cutaneous flare responsiveness (millimeter) elicited, respectively, in comparisons between the Waorani Indians (9806 IU/ml; less than 1.0 mm), Tibetans (2930 IU/ml; 2.06 mm), and North Carolina subjects (108 IU/ml; 4.49 mm). Differences in methacholine sensitivity were small and not significant. A highly significant inverse relationship (r = -0.50, p less than or equal to 0.0001) was detected between the circulating IgE concentrations and the methacholine-induced cutaneous flare responsiveness in this cross-cultural, cross-environmental comparison of three populations.(ABSTRACT TRUNCATED AT 250 WORDS)

The binding of soluble components of pollen grains to plant-stigma receptors can be inhibited by concanavalin A. This lectin-like activity of pollen components is important in the genetic control of plant reproduction. Aqueous extracts of allergenic pollens also react with concanavalin A. Agarose gel-diffusion precipitates were used to survey and characterize the ability of allergenic pollen extracts to react with concanavalin A and other lectins. Concanavalin A alone precipitated with extracts of plantain, American beech, white ash, and corn pollens. Surprisingly, extracts of the pollen from certain plants also precipitated when the extracts were diffused against pollen extracts from other plants. Pollen extracts of alfalfa, white ash, American beech, burweed marsh elder, redtop grass, corn, plantain, orchard grass, and aspen reacted with one or more other pollen extracts. Extract precipitin activity was reliably obtained after extracting pollens for 20 min with pH 7.5, 0.05M Tris buffer in 0.2M of saline. Optimal agarose gel conditions for detecting the precipitin reactions were pH 8.5 to 9.0, 75 mM borate buffer made to an ionic strength of 1.5M with NaCl for concanavalin A pollen reactions and 0.015M with NaCl for pollen-pollen reactions. The presence of the borate ion was necessary for optimal detection of the agarose gel precipitates. Studies of the inhibition of the lectin-pollen and pollen-pollen reactions with specific mono and disaccharides revealed many similarities and differences between the two types of reactions. The high concentrations of glycerol used to stabilize pollen extracts also inhibit these reactions.

Three hundred seventy-four patients with asthma were entered into a year-long, double-blind, double-placebo controlled study comparing the prophylactic effect of ketotifen (229 patients), theophylline (73 patients), and placebo (72 patients). The ketotifen group was larger to allow the accumulation of additional long-term safety data. The primary measure of therapeutic effect was a decrease in concomitant medication without a significant increase in symptomatology or a decrement in pulmonary functions. A patient daily diary was used to document symptoms (cough, shortness of breath, and wheeze) and concomitant medications taken during the 2-week baseline and the subsequent 12 monthly periods. After 2 months of study-drug therapy, the ketotifen patients had a greater decrease in both concomitant medication and symptomatology than either of the other groups. This delay in the onset of therapeutic activity has been observed in other studies and is characteristic of this compound. The principal side effect observed with ketotifen is initial sedation, which was found to be self-limiting and of little concern to the patient after the first month.

A standard assessment of immunity was accomplished in 15 patients with the polyglandular failure syndrome and compared to similar studies in appropriate healthy controls. The patients exhibited decreased delayed cutaneous responsiveness and increased serum levels of immunoglobulins G and A. Complement fixing antibody titers to a number of common viruses were equivalent to those observed in controls, but titers ot Coxsackie B4 and B5 viruses were decreased in patients. The decreased antibody titers to Coxsackie B4 and B5 represent an alteration in host protection which is of possible importance in the etiology of polyglandular failure.

Mantoux-type skin tests were applied to 29 elderly residents of an intermediate care floor of a nursing home. Eight antigens were used with each resident, and the size of the reactions was measured at 6, 24, 48, and 72 hours. All but one resident had at least one response greater than or equal to 3 mm at 48 or 72 hours, and most had more than one response of that size. At 48 compared with 72 hours, there was one more responder and the mean size of the reactions to each antigen was greatest. However, there were two responders at 72 hours who did not react at 48 hours, and the total number of reactions in the group was greater at the later reading. Only one resident did not produce any response at either 48 or 74 hours. The minimum number of antigens needed to identify all responsive subjects was five (PPD-Avian, coccidioidin, histoplasmin, streptokinase-streptodornase, and trychophytin). The purified protein derivative of tuberculin skin test was repeated on subjects who had an initial response less than 10 mm, and one increase of more than 6 mm was observed in a resident who was initially unresponsive to that antigen.

Genetic control of the response to specific natural-product antigens has been documented in three informative families. Families were selected on the basis of probands with tuberculosarcoidosis, chronic cutaneous moniliasis, and rheumatoid arthritis. An increased incidence of delayed cutaneous unresponsiveness was observed in each family. Positive associations were identified between HL-A haplotypes and immediate cutaneous hypersensitivity responses to 5, 8, and 11 of 23 test antigens in the three respective families. HL-A-associated differences in averaged responses of cutaneous hypersensitivity were excluded. These significant associations are consistent with linkage between HL-A haplotypes and genes responsible for the immune response to various natural-product antigens.