Delayed-onset Reactions Research Articles

Review of Delayed Reactions to 15 Hyaluronic Acid Fillers.

Delayed-onset reactions are increasingly relevant given the growing use of hyaluronic acid dermal fillers. There is poor understanding of the phenomenon's etiology and incidence. To highlight differences between the dermal filler products with an emphasis on delayed-onset reaction incidence, pathogenesis, prevention, and treatment. A literature review was performed for delayed-onset reactions following hyaluronic acid dermal filler injection using PubMeb and Embase. Articles were included based on relevance, quality, and the predetermined definition of "delayed-onset reaction" (>30 days post injection). A total of 28 studies were included in the data analysis. A total of 13,136 subjects from 28 studies treated with 15 filler types were included in the analysis. VYC-15L dermal filler injections carried the highest risk of delayed reaction with a mean incidence of 3.83% ( n = 46/1,202), followed by VYC-20L (0.92%) and VYC-17.5L (0.88%). The mean incidence of delayed reactions among all filler types was 1.13%. Incidence of delayed reaction to hyaluronic fillers ranges from 0% to 3.83% (mean = 1.13%) and varies by filler type. The exact etiology of these delayed reactions remains disputed. Future studies should report reaction description, precise timeline, and posttreatment immunologic history to better delineate the incidence of delayed-onset hypersensitivity reactions.

Herpes zoster following mRNA-1273 COVID-19 vaccination

Sir, Skin rashes have been associated with COVID-19 and studies suggest the inclusion of skin diseases in the list of COVID-19 symptoms. Skin eruptions are also associated with the mRNA-1273 COVID-19 vaccine. Findings by Baden et al. [1] describe immediate injection-site reactions observed in 84.2% of participants after the first dose, with delayed onset reactions—on or after day eight—occurring much more infrequently, 0.8% after the first dose and 0.2% after the second dose. Blumenthal et al. [2] discuss twelve cases of delayed vaccine reactions, with all patients experiencing reactions in the vaccination site. Herein, we describe two cases of herpes zoster within days of receiving their first mRNA-1273 vaccine. Both cases presented to the same dermatology clinic. A 77-year-old male presented with a bumpy, itchy, red rash on the upper right arm and axilla three days following an mRNA-1273 vaccine injection. The symptoms continued to worsen and the patient was clinically diagnosed with herpes zoster and treated with valacyclovir (Fig. 1). Another patient, also a 77-year-old male, complained of a rash located on the right upper arm and axilla. It was a red, itchy, bumpy rash that the patient developed two days after an mRNA-1273 vaccine injection (Fig. 2). Both rashes demonstrated a similar distribution pattern and both patients responded well to valacyclovir with the resolution of the erythema; however, one patient did have residual post-herpetic neuralgia.

Observation and analysis of systemic reactions to house dust mite subcutaneous immunotherapy in 362 patients with allergic rhinitis

Objective: To investigate the frequency and severity of systemic reactions (SRs) to standardized house dust mite subcutaneous immunotherapy (SCIT) in patients with perennial allergic rhinitis (AR), and to analyze the clinical risk factors. Methods: The clinical data of 362 patients including 209 males and 153 females, aged from 5 to 55 years old receiving SCIT at the Department of Otorhinolaryngology, the Third People's Hospital of Changzhou were collected from May 2014 to July 2017. The SRs were classified as early-onset and delayed-onset, and 4 grades (grade Ⅰ to Ⅳ) to assess severity. The records of SRs were retrospectively analyzed, including the numbers/frequencies, symptoms and signs, onset of reaction and treatment. And the relationships between SRs and patient's age, gender, allergen injection dose, accompanied allergic diseases were explored. All the statistical analyses were conducted using SPSS 19.0. Results: There were 57 cases (15.75%) of SRs in 362 patients. All the patients received a total of 12 308 injections and 111 SRs (0.90%) were observed. Among them, 31 (27.93%) were early-onset reactions and 80 (72.07%) were delayed-onset reactions; most of the SRs were grade Ⅰ reactions (n=83, 74.78%), followed by grade Ⅱ (n=25, 22.52%), grade Ⅲ (n=3, 2.70%), and no fatal reactions occurred. The incidence of SRs in patients>14 years old was higher than that in patients ≤14 years old according to the number of cases and injections (35.14% vs 13.54%, 2.34% vs 0.76%, χ(2) value was 11.679, 28.162, respectively, all P<0.05), but no significant differences of SRs were observed in gender (18.66% vs 11.76%, 5.98% vs 5.62%, χ(2) value was 3.166, 0.095, respectively, all P>0.05). Fifteen SRs (13.51%) occurred during the build-up phase and 96 (86.49%) during the maintenance phases. SRs could occur in lots of dose phases, and 95 (85.59%) were distributed at high concentrations more than 40 000 SQ-U. The incidence of SRs in patients with multiple allergic diseases was significantly higher than that in patients with AR alone, with asthma or atopic dermatitis (30.67% vs 11.85%, χ(2)=15.875, P<0.001). Meanwhile, the incidence of SRs in patients with pure AR was also significantly lower than that in patients with other allergic diseases (5.26% vs 20.56%, χ(2)=13.783, P<0.001). Conclusions: The incidence of SRs is less than 1% according to the injection times, the severity of SRs is mostly slight, and the safety and tolerance are good during standardized house dust mite SCIT in perennial AR patients. Delayed-onset SRs are more common. The incidence of SRs is significantly correlated with age, high dose of allergen vaccine injection, and concomitant other allergic diseases (asthma, atopic dermatitis, etc).

Global Approaches to the Prevention and Management of Delayed-onset Adverse Reactions with Hyaluronic Acid-based Fillers.

Background:Delayed-onset adverse reactions to hyaluronic acid (HA) fillers are uncommon but have received increased attention, particularly with regard to late-onset nodules. Globally, there is a need for comprehensive prevention and management strategies.Methods:Experts with clinical practices in diverse regions of the world and extensive experience in managing complications related to HA fillers convened to propose and evaluate approaches to prevent delayed-onset adverse reactions after HA filler administration and manage late-onset nodules.Results:The expert panel agreed to define delayed-onset adverse reactions as those presenting more than 4 weeks posttreatment, with swelling, induration, and nodulation being the most common clinical signs. The panel recommended 5 general key approaches for the prevention of delayed-onset reactions (patient selection, anatomic location of injection/product selection, aseptic technique, injection procedure/filler, and posttreatment care). Strategies recommended for managing late-onset nodules included oral antibiotics, oral steroids, nonsteroidal anti-inflammatory drugs if needed, hyaluronidase for noninflammatory nodules (recognizing the limitations and regional availability of this treatment), intralesional antibiotics, intralesional immunosuppressive drugs such as steroids and fluorouracil, and surgical excision as a last resort. The panel noted that late-onset nodules may vary in both clinical presentation and etiology, making them challenging to address or prevent, and stressed individualized treatment based on clinical presentation. Regional differences in aseptic protocols, antibiotic selection, and steroid formulations were described.Conclusion:Insights from global experts on approaches to prevent and manage delayed-onset adverse reactions following HA filler administration, including late-onset nodules, support clinicians worldwide in optimizing patient outcomes and safety.

Current Epidemiology and Management of Radiocontrast-Associated Acute- and Delayed-Onset Hypersensitivity: A Review of the Literature.

Radiocontrast-associated acute-onset hypersensitivity reactions now occur less frequently than before 1990, when high-osmolar, ionic, radiocontrast agents were widely used. Premedication with corticosteroids and antihistamines does not reliably prevent recurrent low-osmolar radiocontrast-associated acute hypersensitivity reactions. Corticosteroid prophylaxis for acute hypersensitivity currently causes more morbidity than benefit. The specific radiocontrast agent that is associated with a patient's adverse reaction must be displayed in the drug intolerance or drug "allergy" field of their electronic health record to enable effective management and prevention of future reactions. The term iodine allergy should never be used in the context of radiocontrast-associated adverse reactions because it leads to poorer clinical outcomes. The time to onset of the reaction and the nature of the reaction must be noted in enough detail in the drug intolerance comment fields in the electronic health record to determine the potential mechanism for the reaction and to enable selection of the appropriate radiocontrast material for future exposures. Most individuals with a history of radiocontrast agent hypersensitivity can be effectively managed by selecting an alternative radiocontrast agent, without any premedication. Radiology Departments, catheterization laboratories, and all physicians who use parenteral radiocontrast media must have management plans in place to treat severe acute reactions when they occur. Patients should be informed that delayed-onset reactions, mostly benign rashes within one week of exposure, are as common or more common than acute reactions. Future radiocontrast-associated acute and delayed-onset reactions can be minimized, but never completely avoided, by using an appropriate alternative agent.

Comparison of diagnostic tests for suspected cow's milk allergy in children with atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease. A third of pediatric AD patients have also food allergy. Although food challenge test is gold standard test for the diagnosis of food allergies, they should be administered by experienced physicians, considering that the test is time-consuming and carries some risks. Documentation of the efficacies of specific IgE (sIgE), skin prick test (SPT), and atopy patch test (APT) are important for determining the necessity of oral food challenge tests(OFC). Fifty-three AD patients with suspected cow's milk allergy (CMA) were included in our study. Diet-related questions were asked to the patients. Blood samples were taken for measurement of total blood count, total IgE, and milk sIgE. OFC, SPT, and APT were performed using pasteurized cow milk. The mean age of the study population was 1.4±0.8 years, and the male:female ratio was 1.12. Cow milk allergy was detected in 45.3% of the patients after OFC. A comparison between CMA(+) and CMA(-) patients revealed no significant difference in sIgE positivity (P=0.940), but there was a significant difference in SPT (P=0.000) and APT (P=0.001) positivity. When our study group was divided into immediate reaction, delayed onset reaction, and not reactive subgroups after OFC, efficacy of SPT was more prominent in immediate reaction subgroup while APT was more efficient in delayed reaction subgroup. Our study showed that using SPT test with APT test in allergic reactions with IgE and other mechanisms such as AD will increase the diagnostic yield, thereby reducing the need for OFC.

4. Food allergy in childhood

Food allergies in children present with a wide spectrum of clinical manifestations, including anaphylaxis, urticaria, angioedema, atopic dermatitis and gastrointestinal symptoms (such as vomiting, diarrhoea and failure to thrive). Symptoms usually begin in the first 2 years of life, often after the first known exposure to the food. Immediate reactions (occurring between several minutes and 2 hours after ingestion) are likely to be IgE-mediated and can usually be detected by skin prick testing (SPT) or measuring food-specific serum IgE antibody levels. Over 90% of IgE-mediated food allergies in childhood are caused by eight foods: cows milk, hens egg, soy, peanuts, tree nuts (and seeds), wheat, fish and shellfish. Anaphylaxis is a severe and potentially life-threatening form of IgE-mediated food allergy that requires prescription of self-injectable adrenaline. Delayed-onset reactions (occurring within several hours to days after ingestion) are often difficult to diagnose. They are usually SPT negative, and elimination or challenge protocols are required to make a definitive diagnosis. These forms of food allergy are not usually associated with anaphylaxis. The mainstay of diagnosis and management of food allergies is correct identification and avoidance of the offending antigen. Children often develop tolerance to cows milk, egg, soy and wheat by school age, whereas allergies to nuts and shellfish are more likely to be lifelong.

A Randomized, Evaluator-Blind, Multicenter Comparison of the Efficacy and Tolerability of Perlane versus Zyplast in the Correction of Nasolabial Folds

Bovine collagen is widely used as a dermal filler for facial soft-tissue augmentation, but it provides only temporary cosmetic improvement. Nonanimal stabilized hyaluronic acid has reduced potential for immunogenicity and hypersensitivity and may provide a more durable aesthetic result. Sixty-eight patients with prominent nasolabial folds were randomized to intradermal treatment with nonanimal stabilized hyaluronic acid gel (Perlane) and bovine collagen (Zyplast) on contralateral sides of the face. On achievement of "optimal cosmetic result" (baseline), patients were followed up for 6 months; bilateral retreatment with Perlane was offered at 6 or 9 months after baseline. Responses were evaluated at 2, 4, 6, 9, and 12 months after baseline. Investigator-based and patient-based ratings indicated that Perlane was more effective than Zyplast in maintaining cosmetic correction. According to investigator-based Wrinkle Severity Rating Scale assessments at 6 and 9 months after baseline, Perlane was superior in 50.0 percent and 48.8 percent of patients, respectively, whereas Zyplast was superior in 10.3 percent and 14.0 percent of patients, respectively (p < 0.0004). Investigator-based Global Aesthetic Improvement Scale assessment at 9 months after baseline indicated that Perlane was superior in 48.8 percent of patients, whereas Zyplast was superior in 14.0 percent of patients (p = 0.0025). "Optimal cosmetic result" was achieved with a smaller volume of Perlane than Zyplast (mean, 1.2 ml versus 2.1 ml). Local injection-site reactions (redness, swelling, pruritus, and induration) were less frequent with Perlane than with Zyplast. Delayed-onset reactions were rare and did not reoccur after Perlane retreatment. Perlane has acceptable long-term safety and offers a longer-lasting aesthetic improvement than Zyplast.

Concurrent cereal allergy in children with cow's milk allergy manifested with atopic dermatitis.

There is increasing consensus about the significance of food allergens in the pathogenesis of atopic dermatitis (AD) in infancy and childhood, with cow's milk and egg accounting for most of the reactions. Previous studies have indicated that multiple food sensitization, such as cereals, is very common in patients with cow's milk allergy (CMA). Evidence is lacking, however, as to its clinical relevance. The purpose of this study was to determine the concurrent occurrence of cereal allergy among children with challenge-proven CMA who have residual symptoms, such as AD and/or gastrointestinal symptoms, during cow's milk elimination diet. Further, we sought to evaluate the utility of patch testing in prescreening foods other than cow's milk behind allergic symptoms in children. The study population comprised 90 children, aged from 2.5 to 36 months (mean 1.1 years), with challenge-proven CMA. As a result of residual symptoms during meticulous cow's milk elimination diet (AD: n=80, and gastrointestinal: n=10), the children were put on a cereal elimination diet (oats, wheat, rye, and barley) and skin prick tests (SPT) and patch testing with cereals were performed. Open cereal challenge was performed to confirm cereal allergy. Cereal challenge was positive in 66 (73%) of the children with CMA. Of them, 17% reacted with immediate reactions and delayed-onset reactions were seen in 83% of the children. SPT was positive in 23%, patch test in 67%, and either SPT or patch test was positive in 73% of the children with cereal allergy. SPT gave the best positive predictive value, whereas SPT together with patch test gave the best negative predictive value. Residual symptoms, such as eczema or gastrointestinal symptoms in CMA children may be a sign of undetected allergy to other food antigens. SPT with cereals aids in diagnosing cereal allergy in small children, especially when used together with patch testing.

Mechanisms in contact urticaria

This chapter provides a brief introduction to the advances and understanding associated with contact urticaria syndrome (CUS; immediate contact reactions). It comprises a wide range of inflammatory reactions that habitually appear within minutes after cutaneous or mucosal contact with the causal agent and disappear within 24 h after contact. However, delayed-onset reactions appearing several hours after exposure are sometimes observed. CUS usually displays a broad spectrum of clinical manifestations ranging from mild erythema and/or itching or burning to severe anaphylactic reactions and even death. It has been reported following skin contact with a multitude of substances ranging from simple chemicals to macromolecules. Its prevalence among the general population is unknown, but it may be a relatively common and under-recognized phenomenon. Contact urticaria (CU) usually clears spontaneously, usually in a few hours; repeated exposure may lead to dermatitis (eczema). In addition, CU may be associated with allergic contact dermatitis (type IV hypersensitivity). Assessing and managing the occupational health risks posed by the use of pesticides in agriculture is a complex but essential task for occupational health specialists and toxicologists. Increased awareness of the signs and symptoms of CUS will lead to increased frequency of diagnosis, which is especially important for ICU. Product information formulated by the registrant would help the health care community (and the worker/patient) by including what is known (and not known) of the potential for developing immunologic and nonimmunologic contact urticaria.

Combined skin prick and patch testing enhances identification of food allergy in infants with atopic dermatitis

BACKGROUND: Early recognition of dietary allergies in infants with atopic dermatitis is essential for avoidance of unnecessary elimination diets, amelioration of the skin disease, and secondary prevention of the development of multiple food allergies. Simple and accurate methods of identifying provocative foods are urgently needed. METHODS: The usefulness of skin prick and patch tests as indicators of cow milk allergy was evaluated in 183 patients ranging in age from 2 to 36 months with double-blind, placebo-controlled ( n = 118) or open ( n = 65) cow milk challenges. RESULTS: The oral cow milk challenges were interpreted as positive in 54% of both challenge types. Positive challenge rapidly elicited pruritus, urticaria, and/or exanthema in 49% of cases and delayed-onset eczematous lesions in 51%. The skin prick and patch tests gave markedly discrepant results; prick tests were positive in 67% of the cases with acute-onset reactions to milk challenge, whereas patch tests tended to be negative. Patch tests were positive in 89% of those with delayed-onset reactions, although prick tests were frequently negative. CONCLUSIONS: The observations indicate that IgE and T cell-mediated responses to cow milk can be distinguished in atopic dermatitis. Parallel skin testing with combined prick and patch tests can significantly enhance the accuracy in diagnosis of specific dietary allergies in patients with atopic dermatitis. (J A LLERGY C LIN I MMUNOL 1996;97:9-15.)

Validation of a non‐invasive technique to assess immediate or delayed onset of airway hypersensitivity in guinea‐pigs

Conscious Hartley guinea-pigs were sensitized with trimellitic anhydride (TMA) or trimeric hexamethylene diisocyanate biuret (Des-N) by repeated intradermal injections or by inhalation exposure. Immediate- and delayed-onset pulmonary reactions were recorded during/after challenges with the hapten or protein conjugate of the hapten, respectively. The positive control was sensitized and challenged with ovalbumin (OA) by inhalation. Homocytotropic antibodies of the IgG1 type were determined to correlate antibody titres and pulmonary responses. Immediate-onset pulmonary reactions were apparent in guinea-pigs sensitized by inhalation of TMA and OA. Animals sensitized intradermally with TMA demonstrated more vigorous immediate-onset reactions than animals sensitized by inhalation. The measurement of breathing parameters demonstrated that the ability to detect immediate-onset airway hyperreactivity was best when the breathing rate and tidal and minute volumes were measured. None of the measurements for delayed-onset reactions presented conclusive results, since sensitized as well as naive guinea-pigs demonstrated a delayed increase of breathing frequency. Antigen-specific IgG1 antibodies were several orders of magnitude higher in intradermally sensitized animals compared with animals sensitized by inhalation. Although Des-N-sensitized guinea-pigs experienced high IgG1-antibody titres, no response of pulmonary hypersensitivity could be elicited after hapten or conjugate challenge. In summary, it would appear that pulmonary hypersensitivity depends on factors other than IgG1 antibody titres. For the screening of chemicals, the dermal induction and inhalation challenge protocol was revealed to be more sensitive than the inhalation induction and inhalation challenge protocol.

Delayed immunologic food reactions.

Delayed onset reactions to ingested foods may be difficult to recognize, especially if days or weeks elapse before symptoms appear. More than one immunologic mechanism may be involved and it is often difficult to assess the relative importance of each. Because immunologic responses occur in many healthy subjects who readily tolerate a specific food, little importance can be ascribed to a particular immunologic test unless it is shown that at least 95% of normals with similar exposure do not have such a response. Each food contains multiple antigens and allergic individuals differ considerably both in their immune responses and in the clinical manifestations they display. Because of this, the recognition and management of delayed food reactions is complex and requires an awareness of documented food-related disorders. It is a fruitful area for future research.

Immunotoxicologic evaluation of the respiratory system: Animal models for immediate- and delayed-onset pulmonary hypersensitivity

A wide variety of industrial materials is known to cause allergic pulmonary reactions. Respiratory symptoms may occur either immediately upon exposure to the agent (immediate-onset response), or several hours later (delayed-onset reaction). In order to determine both the mechanism of response, and a safe exposure level which would prevent development of pulmonary sensitization, animal models are currently being developed for both types of sensitivity responses. In the models, emphasis is placed on simulating conditions present in the industrial environment. For example, (1) exposure to agents is via the inhalation route, (2) animals are unrestrained and unanesthetized both during exposure and during elicitation of response, and (3) reactive chemicals, as opposed to hapten-protein conjugates, are used for exposure. In the model for immediate-onset sensitivity, concentration-response relationships have been observed between the concentration of agent inhaled and the percentage of animals becoming sensitized. Agents employed were bacterial subtilisin and toluene diisocyanate. Identification of “no observable effect” threshold concentrations implies that exposure levels can be proposed for industrial chemicals which will not result in sensitization of workers. Further development of the animal models, followed by calibration of the models to humans, should allow immunotoxicologic evaluation of chemicals for their respiratory sensitizing ability and recommendation of threshold-limit values (TLVs) which would prevent sensitization.

Cows' milk hypersensitivity: immediate and delayed onset clinical patterns.

The clinical patterns of adverse reactions to cows' milk were examined in 72 children with cows' milk hypersensitivity. Two main groups were found, according to the time of onset of the adverse reaction--immediate onset, within one hour of milk ingestion and delayed onset, after one hour. Children with immediate onset reactions usually had cutaneous manifestations, positive prick tests, raised IgE values, were atopic, and the reaction was provoked by only small amounts of milk. Children with delayed onset reactions usually had gastrointestinal manifestations; negative prick tests; normal IgE values; were not atopic; had a history of vomiting, diarrhoea, and colic in the first year of life; and a larger amount of milk was needed to provoke the adverse reaction. Placing affected children into one or other category should increase the reliability of interpreting milk prick tests and clinical findings.

Local Transfer of Delayed Hypersensitivity and Cutaneous Basophil Hypersensitivity

Abstract We have studied the capacity of unfractionated cells, or of purified populations of T and B cells, prepared from the lymph nodes of sensitized guinea pigs with classical delayed hypersensitivity (DH) or with cutaneous basophil hypersensitivity (CBH), to induce reactions in normal syngeneic guines pigs after intradermal injection with antigen (ovalbumin, DNP-BGG, or α,DNP-Lysine11). Injections of cells or antigen alone produced little or no reaction. Injections of antigen and cells from DH donors resulted in delayed onset reactions, which were indurated and which usually contained only a few basophils. With cells from CBH donors, delayed onset reactions were also produced, but these were less indurated and the infiltrate generally contained higher percentages of basophils. Thus, the reactions resembled those in actively immunized animals. With cells from DH donors, reactions were consistently produced with unfractionated cells or T cell preparations, with cell doses as low as 0.5 to 1 × 106. B cell preparations also produced reactions, but only with higher cell doses (2 to 3 × 106); these reactions were probably due to contaminating T cells. With cells from CBH donors, reactions were consistently produced with unfractionated cells, T or B cell preparations in the dose range of 2 to 3 × 106 cells. There was no lower dose at which reactions resulting from B cell preparations could be eliminated while still retaining T cell reactivity. Moreover, doubly purified B cell preparations, with 98% Ig-positive cells, were as effective as singly purified preparations (95% Ig positive). These findings indicate that both T and B cells can initiate CBH reactions and support the interpretation that CBH reactivity is heterogeneous.

Cutaneous basophil hypersensitivity

Cutaneous basophil hypersensitivity (CBH) is a distinct form of lymphocyte-mediated hypersensitivity in guinea pigs, separate both from classic delayed hypersensitivity (DH) and from the well-known antibody-mediated reactions. CBH, not DH, is the usual cellular immune response of this species to a wide variety of immunogens (e.g., allografts, certain parasites, and viruses) when these are presented in native form without supplementation with mycobacteria-containing adjuvants, thus attesting to the importance of this response in the guinea pig's overall immune defense mechanism. Basophil-containing, cell-mediated, delayed-onset reactions occur in other species, including man, as well.

Differences in sensitivity to a cytotoxic anti-thymus-derived lymphocyte serum of cells mediating delayed-onset reactions in guinea pigs to hapten-protein conjugates and contactants

Lymph node cells from guinea pigs immunized with a reactive dinitrophenyl (DNP) compound in complete Freund's adjuvant were treated with a cytotoxic anti-guinea pig thymus-derived lymphocyte (T cell) antiserum prior to transfer to unimmunized recipients to study the functional cell types active in mediating delayed-onset hypersensitivities. Attempts were also made to block the passive transfer of delayed-onset sensitivities with an anti-guinea pig κ chain serum. The data indicate that delaye-donset sensitivities to contactant and to PPD are mediated by T cells easily killed by a high dilution of anti-T cell serum but not affected by a low dilution of anti-κ chain serum. Surprisingly, the delayed-onset response to DNP conjugates was undiminished after treatment with anti-T cell serum which suggests that this sensitivity is not mediated by cells mediating the other delayed-onset sensitivities. In both actively and passively sensitized animals, contact sensitivity was highly specific for DNP; in contrast, delayed-onset sensitivity to conjugates was elicited nearly as well by DNP as by TNP conjugates, a characteristic cross-reactivity often seen in serum antibodies to DNP. Despite the differences among them, all three types of delaye-donset sensitivity were cell-mediated and could not be passively transferred by heat-killed cells or serum.

Morphologic Changes in Draining Lymph Nodes and in Lymphocyte Cultures after Sensitization with Complete or Incomplete Freund's Adjuvant. Correlation with Immunologic Events in Vivo and in Culture

Abstract Morphologic changes occurring in draining lymph nodes were studied at two intervals after sensitization of guinea pigs with human serum albumin (HSA) in complete or incomplete Freund's adjuvant (CFA or IFA) and were correlated with the immunologic response of these animals. At 1 week after sensitization with HSA in IFA guinea pigs were primed for the delayed-onset reactions of cutaneous basophil hypersensitivity (CBH) but had little circulating antibody. Their lymph nodes manifested paracortical cell hyperplasia with a striking degree of blast transformation, and cells from such nodes, cultured in the presence of antigen, incorporated 3H-thymidine at an enhanced rate and underwent morphologic blast transformation. At 6 weeks, these animals had lost CBH skin reactivity but had high titers of circulating antibody. Draining lymph nodes contained prominent germinal centers and numerous plasma cells, but paracortical blasts had returned to control levels, and isolated cells were not stimulated to incorporate thymidine by antigen in culture. By contrast, animals sensitized with the same antigen in CFA developed progressively indurated skin reactions characteristic of delayed hypersensitivity (DH), as well as high titers of circulating antibody. In draining lymph nodes, blast cells outside of germinal centers were never as numerous as at 1 week following administration of antigen in IFA; however, a significant number persisted at 6 weeks when excellent antigen-induced thymidine incorporation and blast transformation could be achieved in culture. Taken together, these data provide additional evidence for the existence of two distinguishable forms of cellular immunity, DH and CBH, and define certain properties of each.