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PURPOSE The immunogenicity and reactogenicity of SARS-CoV-2 vaccines in patients with cancer are poorly understood. METHODS We performed a prospective cohort study of adults with solid-organ or hematologic cancers to evaluate anti–SARS-CoV-2 immunoglobulin A/M/G spike antibodies, neutralization, and reactogenicity ≥ 7 days following two doses of mRNA-1273, BNT162b2, or one dose of Ad26.COV2.S. We analyzed responses by multivariate regression and included data from 1,638 healthy controls, previously reported, for comparison. RESULTS Between April and July 2021, we enrolled 1,001 patients; 762 were eligible for analysis (656 had neutralization measured). mRNA-1273 was the most immunogenic (log10 geometric mean concentration [GMC] 2.9, log10 geometric mean neutralization titer [GMT] 2.3), followed by BNT162b2 (GMC 2.4; GMT 1.9) and Ad26.COV2.S (GMC 1.5; GMT 1.4; P < .001). The proportion of low neutralization (< 20% of convalescent titers) among Ad26.COV2.S recipients was 69.9%. Prior COVID-19 infection (in 7.1% of the cohort) was associated with higher responses ( P < .001). Antibody titers and neutralization were quantitatively lower in patients with cancer than in comparable healthy controls, regardless of vaccine type ( P < .001). Receipt of chemotherapy in the prior year or current steroids were associated with lower antibody levels and immune checkpoint blockade with higher neutralization. Systemic reactogenicity varied by vaccine and correlated with immune responses ( P = .002 for concentration, P = .016 for neutralization). In 32 patients who received an additional vaccine dose, side effects were similar to prior doses, and 30 of 32 demonstrated increased antibody titers (GMC 1.05 before additional dose, 3.17 after dose). CONCLUSION Immune responses to SARS-CoV-2 vaccines are modestly impaired in patients with cancer. These data suggest utility of antibody testing to identify patients for whom additional vaccine doses may be effective and appropriate, although larger prospective studies are needed.

After initial reports of anaphylaxis to the messenger RNA (mRNA) COVID-19 vaccines, the Centers for Disease Control and Prevention (CDC) put forth guidance stating that patients with a history of anaphylaxis to vaccine components like polyethylene glycol (PEG) should not receive the mRNA COVID-19 vaccines.1 To address this clinical challenge and decrease vaccine hesitancy, we published an approach to guide COVID-19 vaccination in high-risk allergy individuals.2-4 While the etiology of anaphylaxis to mRNA COVID-19 vaccines remains unclear, PEG continues to be an important focus.5,6 Paclitaxel contains polyoxyl-35 castor oil --a PEG derivative and structurally similar to the excipient in Pfizer-BioNTech and Moderna COVID-19 vaccines-- and docetaxel contains polysorbate 80 --the excipient in Janssen COVID-19 vaccine. Given this, we sought to assess the utility of pre-vaccine excipient skin testing (ST), risk stratification and COVID-19 vaccine tolerability in oncology patients with a history of paclitaxel or docetaxel hypersensitivity reaction (HSR).

Large clinical trials have demonstrated the overall safety of vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, reports have emerged of autoimmune phenomena, including vaccine-associated myocarditis,1 immune thrombocytopenia,2 and immune thrombotic thrombocytopenia.3 4 Here we present a novel case of a young woman who developed life-threatening autoimmune hemolytic anemia (AIHA) after her first dose of a SARS-CoV-2 mRNA vaccine. Notably, initial direct antiglobulin testing was negative using standard anti-IgG reagents, which are "blind" to certain immunoglobulin (IgG) isotypes. Further testing using an antiglobulin reagent that detects all IgG isotypes was strongly positive and confirmed the diagnosis of AIHA. The patient required transfusion with 13 units of packed red blood cells, as well as treatment with corticosteroids, rituximab, mycophenolate mofetil, and immune globulin. As efforts to administer SARS-CoV-2 vaccines continue globally, clinicians must be aware of potential autoimmune sequelae of these therapies. This article is protected by copyright. All rights reserved.

Background Nonsteroidal anti-inflammatory drug (NSAID) outpatient challenge protocols are not standardized, vary in clinical practice, and can be time and resource intensive to perform. Objective Investigate the safety and outcomes of two-step outpatient NSAID challenges for evaluation of patients with non-aspirin-exacerbated respiratory disease (AERD)-related NSAID hypersensitivity. Methods We conducted a retrospective study of patients with history of NSAID allergy who underwent outpatient NSAID challenges under allergist supervision. Individuals with AERD were excluded. Patient demographics, NSAID reaction history and drug challenge details and outcomes were collected. Results A total of 249 patients (mean age 51.6 years, 63.5% female) underwent 262 NSAID challenges. Of these, 224 (85.5%) challenges were negative. There were 30 challenges (11.5%) that resulted in an immediate reaction during the challenge procedure, and 8 (3.1%) that resulted in delayed reactions. Three individuals with immediate reactions required treatment with intramuscular epinephrine. Factors associated with a positive NSAID challenge included a prior reaction occurring within 5 years of drug challenge (Odds Ratio [OR] 3.66, 95% CI 1.67-8.44), history of a prior immediate reaction within 3 hours of NSAID ingestion (OR 2.45, 95% CI 1.12-5.57), history of cross-reactive NSAID hypersensitivity to multiple NSAIDs (OR 2.97, 95% CI 1.23-6.91), and presence of comorbid chronic spontaneous urticaria (OR 2.95, 95% CI 1.35-6.41). Conclusion Over 85% of two-step non-AERD NSAID drug challenges were negative for an immediate or delayed reaction, opening up patients for use of at least one clinically indicated NSAID. Challenge reactions were generally mild. Two-step NSAID challenge protocols can be safely performed in the outpatient setting.

Background The Centers for Disease Control and Prevention state that a severe or immediate allergic reaction to the first dose of an mRNA COVID-19 vaccine is a contraindication for the second dose. Objective To assess outcomes associated with excipient skin testing after a reported allergic reaction to the first dose of mRNA COVID-19 vaccine. Methods We identified a consecutive sample of patients with reported allergic reactions after the first dose of mRNA COVID-19 vaccine who underwent allergy assessment with skin testing to polyethylene glycol (PEG) and, when appropriate, polysorbate 80. Skin testing results in conjunction with clinical phenotyping of the first-dose mRNA COVID-19 vaccine reaction guided second-dose vaccination recommendation. Second-dose mRNA COVID-19 vaccine reactions were assessed. Results Eighty patients with reported first-dose mRNA COVID-19 vaccine allergic reactions (n = 65; 81% immediate onset) underwent excipient skin testing. Of those, 14 (18%) had positive skin tests to PEG (n = 5) and/or polysorbate 80 (n = 12). Skin testing result did not affect tolerance of the second dose in patients with immediate or delayed reactions. Of the 70 patients who received the second mRNA COVID-19 vaccine dose (88%), 62 had either no reaction or a mild reaction managed with antihistamines (89%), but 2 patients required epinephrine treatment. Three patients with positive PEG-3350 intradermal (methylprednisolone) testing tolerated second-dose mRNA COVID-19 vaccination. Refresh Tears caused nonspecific skin irritation. Conclusions Most individuals with a reported allergic reaction to the first dose of mRNA COVID-19 vaccines, regardless of skin test result, received the second dose safely. More data are needed on the value of skin prick testing to PEG (MiraLAX) in evaluating patients with mRNA COVID-19 vaccine anaphylaxis. Refresh Tears should not be used for skin testing.

The U.S. Food and Drug Administration (FDA) has recently issued an Emergency Use Authorization (EUA) for 2 highly effective coronavirus disease 2019 (COVID-19) vaccines from Pfizer-BioNTech and Moderna. This has brought hope to millions of Americans in the midst of an ongoing global pandemic. The FDA EUA guidance for both vaccines is to not administer the vaccine to individuals with a known history of a severe allergic reaction (eg, anaphylaxis) to any component of the COVID-19 vaccine. The Centers for Disease Control and Prevention (CDC) additionally advises individuals with a history of an immediate allergic reaction to a vaccine or injectable or any history of anaphylaxis be observed for 30 minutes after COVID-19 vaccination. All other individuals should be observed for 15 minutes after COVID-19 vaccination. Staff at vaccine clinics must be able to identify and manage anaphylaxis. Post–FDA EUA, despite very strong safety signals in both phase 3 trials, reports of possible allergic reactions have raised public concern. To provide reassurance and support during widespread global vaccination, allergists must offer clear guidance to individuals based on the best information available, but also in accordance with the broader recommendations of regulatory agencies. This review summarizes vaccine allergy epidemiology and proposes drug and vaccine allergy expert opinion informed risk stratification for Allergy specialist use in conjunction with guidance of public health and regulatory authorities. The risk stratification schema guide care for (1) individuals with different allergy histories to safely receive their first mRNA COVID-19 vaccine and (2) individuals who develop a reaction to their first dose of mRNA COVID-19 vaccine.

Delayed Local Reactions to mRNA-1273 Vaccine Delayed cutaneous reactions developed in 12 patients days after initial injection-related symptoms resolved. The reactions, some as severe as grade 3, r...

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with predominant antibody deficiency (PAD) is associated with high morbidity, yet data regarding the response to SARS-CoV-2 immunization in PAD patients, including additional dose vaccine, are limited.To characterize antibody response to SARS-CoV-2 vaccine in PAD patients and define correlates of vaccine response.We assessed the levels and function of anti-SARS-CoV-2 antibodies in 62 PAD patients compared with matched healthy controls at baseline, at 4 to 6 weeks after the initial series of immunization (a single dose of Ad26.COV2.S [Janssen] or two doses of BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]), and at 4 to 6 weeks after an additional dose immunization, if received.After the initial series of SARS-CoV-2 vaccination, PAD patients had lower mean anti-spike antibody levels compared with matched healthy controls (140.1 vs 547.3 U/mL; P = .02). Patients with secondary PAD (eg, B-cell depletion therapy was used) and those with severe primary PAD (eg, common variable immunodeficiency with autoinflammatory complications) had the lowest mean anti-spike antibody levels. Immune correlates of a low anti-spike antibody response included low CD4Patients with secondary and severe primary PAD, characterized by low T helper cells, low B cells, and/or low class-switched memory B cells, were at risk for low antibody response to SARS-CoV-2 immunization, which improved after an additional dose vaccination in most patients.

Background Allergic drug reaction epidemiologic data are sparse because it remains difficult to identify true cases in large data sets using manual chart review. Objective To develop and validate a novel informatics method based on natural language processing (NLP) in combination with International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes that identifies allergic drug reactions in the electronic health record. Methods Previously studied and high-yield ICD-9-CM codes were used to screen for possible allergic drug reactions among all inpatients admitted in 2007 and 2008. A random sample was selected for manual chart review to identify true cases of allergic drug reactions. A rule-based NLP algorithm was then developed to identify allergic drug reactions using free-text clinical notes and discharge summaries from the filtered cases. The performance of using manual chart review of ICD-9-CM codes alone was compared with ICD-9-CM codes in combination with NLP. Results Of 3907 cases identified by ICD-9-CM codes, 725 (19%) were randomly selected for manual chart review; 335 were confirmed as allergic drug reactions, resulting in a positive predictive value (PPV) of 46% (range: 18%-79%) when using ICD-9-CM codes alone. Our NLP algorithm in combination with ICD-9-CM codes achieved a PPV of 86% (range: 69%-100%). Among the 335 confirmed positive cases, NLP identified 259 true cases, resulting in a recall/sensitivity of 77% (range: 26%-100%). Among the 390 negative cases, NLP achieved a specificity of 89% (range: 69%-100%). Conclusion Using NLP with ICD-9-CM codes improved identification of allergic drug reactions. The resulting decrease in manual chart review effort will facilitate large epidemiology studies of this understudied area.

Background For patients with a history of drug hypersensitivity reaction (HSR) during anesthesia, strategies to minimize risk with subsequent anesthesia are unclear. Identification of the cause of HSR during anesthesia remains challenging. Objective To determine the success of a comprehensive allergy evaluation and management plan for patients with HSR during anesthesia, including identification of the causative agent and review of outcomes during subsequent anesthesia exposure. Methods We performed chart reviews of patients referred for the evaluation of HSR during anesthesia between 2003 and 2012. Data collection included patient characteristics, signs/symptoms of HSR during anesthesia, and subsequent outcomes. Patients underwent comprehensive allergy evaluation including skin testing for identifying potential culprit agents, and the results were used to provide recommendations for any subsequent anesthesia. Results Over the 10-year study period, 73 patients with HSR during anesthesia were referred for further evaluation. Thirteen patients (18%) had positive skin test results to a drug received during anesthesia. One patient with a positive skin test result was diagnosed with mastocytosis. The causative agents identified in these 13 patients included latex, β-lactam antibiotics, neuromuscular blockers, tetracaine, odansetron, and fentanyl. On follow-up, 47 of the 73 patients (64%) subsequently underwent procedures requiring anesthesia. Using our recommendations from evaluation and testing, 45 of these 47 patients (96%) successfully tolerated subsequent anesthesia. The 2 patients who developed recurrent HSR during anesthesia were later diagnosed with mast cell disorders. Conclusions Our comprehensive evaluation and management plan minimizes risk with subsequent anesthesia even when the cause of HSR could not be identified. Baseline tryptase levels may be helpful in this patient population to diagnose mast cell disorders.

Because of widespread use, nonsteroidal anti-inflammatory drugs (NSAIDs) are the second most common cause of all adverse drug reactions, with hypersensitivity reported in ∼1% of the population. NSAID hypersensitivity can be categorized into five types by the underlying disease, symptoms of reaction, and timing of reaction. These include rhinitis and asthma induced by NSAIDs (also known as aspirin-exacerbated respiratory disease), NSAID-exacerbated cutaneous disease (NECD), urticaria or angioedema induced by multiple NSAIDs, single NSAID-induced reactions, and delayed NSAID reactions. NECD occurs in one-third of patients with chronic urticaria who develop an exacerbation of their urticaria, sometimes with angioedema, typically beginning 30-90 minutes after ingestion of NSAIDs that inhibit cyclooxygenase (COX)-1. In urticaria or angioedema induced by multiple NSAIDs, patients without underlying disease develop urticaria or angioedema 30-90 minutes after ingestion of COX-1-inhibiting NSAIDs including aspirin. Single NSAID-induced reactions are immediate and specific to a single NSAID and are thought to occur because of an IgE-mediated reaction against a specific epitope of the NSAID. Delayed NSAID reactions occur days to weeks after initiating an NSAID. These are T-cell mediated and not amenable to desensitization or rechallenge. Classifying the type of NSAID hypersensitivity is important because many patients with a prior history of urticaria or angioedema induced by multiple NSAIDs will often tolerate aspirin test dose. This would allow the use of an aspirin for primary or secondary prevention in patients with coronary artery disease despite a presumed history of NSAID hypersensitivity.

Background Graded challenges are the criterion standard for evaluating adverse drug reactions (ADR). Evidence-based guidelines regarding the optimal number of steps for challenges are lacking. Objective To determine the safety and outcomes of 1- or 2-step test doses among patients with ADRs seen by the allergy/immunology consult service and to compare the outcomes of 1- or 2-step test doses with multistep challenges performed during the same time period. Methods We conducted a retrospective chart review of all 1- or 2-step test doses and multistep challenges at a single academic center between 2008 and 2013. Patient demographics, symptoms of initial ADRs, and outcomes of test doses and multistep challenges were reviewed. ADRs were classified by type and were graded by severity. Outcomes of 1- or 2-step test doses were compared with multistep challenges. Results We identified 456 patients who underwent 497 one- or 2-step test doses (mean age, 51 years; 67.5% female patients). The most common drugs that prompted test doses were β-lactams (62%). The majority of patients (n = 444 [89%]) did not experience any ADRs during test doses. ADRs that occurred during test doses (n = 53 [11%]) were most commonly non-immune-mediated (45%) or IgE-mediated (32%), with grade 1 or 2 severity (100%). Forty-nine percent of ADRs during test doses did not receive any treatment. The ADR rate during multistep challenges (10/82 [12%]) was similar to test doses. Conclusion One- or 2-step test doses were safe for evaluation of ADRs. Multistep challenges did not confer added safety. Furthermore, 1- or 2-step test doses did not raise concern for induction of tolerance.

Multiple drug allergy syndrome (MDAS) is a clinical diagnosis made in patients with adverse reactions to two or more structurally unrelated drugs with an underlying immune-mediated mechanism causing the reaction. The evaluation of a patient with MDAS begins with a comprehensive drug allergy history and consideration of the underlying immune mechanism for each reaction. Skin testing is a useful diagnostic tool; however, the only validated immediate hypersensitivity skin testing is for penicillin where the antigenic determinants have been identified. Skin testing to most other drugs, although not validated, can be considered using a nonirritating concentration (NIC). In general, skin test positivity using an NIC suggests that the drug should be avoided, but a negative result does not rule out an IgE-mediated allergy. A test dose, also called a drug provocation test, graded oral challenge, or incremental challenge, should be performed when there is a low likelihood of an IgE-mediated mechanism for the reaction. In patients with a recent IgE-mediated hypersensitivity reaction or positive skin testing with no reasonable alternative treatment options, desensitization protocols can be used to allow the patient to safely receive a necessary drug. The evaluation of patients with MDAS is both challenging and time-consuming for the practicing allergist, who must systematically evaluate each reaction to help determine which drugs can be safely used again in the future. The molecular mechanisms and risk factors for this condition remain poorly understood, but research to further understand this condition is ongoing.

Background The study of allergic drug reactions has been limited because of challenges in identifying and confirming cases. Objective To determine the utility of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for identifying inpatient allergic drug reactions and to compare findings with previous data in the emergency department. Methods By reviewing medical records of inpatients with ICD-9-CM codes and E codes suggestive of allergic drug reactions at a large urban academic medical center, we determined codes that yielded the most drug allergy cases and identified culprit drugs. Results In 2005 and 2010, 3337 and 5282 possible allergic drug reactions during hospitalization were identified and 1367 were reviewed. Allergic drug reactions were found in 409 (30.1%) of the reviewed charts, with 172 (29.7%) in 2005 and 237 (30.5%) in 2010. The codes that identified the highest percentage of true allergic drug reactions were dermatitis due to drug (693.0), allergic urticaria (708), angioneurotic edema (995.1), and anaphylaxis (995.0). Antibiotics were the most common cause (44.4%); however, multiple drug classes were often identified as likely culprit drugs. Conclusion Specific ICD-9-CM codes can identify patients with allergic drug reactions, with antibiotics accounting for almost half of true reactions. Most patients with codes 693.0, 995.1, 708, and 995.0 had allergic drug reactions, with 693.0 as the highest yield code. An aggregate of multiple specific codes consistently identifies a cohort of patients with confirmed allergic drug reactions.

Glaucoma, the most frequent optic neuropathy, is a leading cause of blindness worldwide. Death of retinal ganglion cells (RGCs) occurs in all forms of glaucoma and accounts for the loss of vision, however the molecular mechanisms that cause RGC loss remain unclear. The pro-apoptotic molecule, Fas ligand, is a transmembrane protein that can be cleaved from the cell surface by metalloproteinases to release a soluble protein with antagonistic activity. Previous studies documented that constitutive ocular expression of FasL maintained immune privilege and prevented neoangeogenesis. We now show that FasL also plays a major role in retinal neurotoxicity. Importantly, in both TNFα triggered RGC death and a spontaneous model of glaucoma, gene-targeted mice that express only full-length FasL exhibit accelerated RGC death. By contrast, FasL-deficiency, or administration of soluble FasL, protected RGCs from cell death. These data identify membrane-bound FasL as a critical effector molecule and potential therapeutic target in glaucoma.

Background The epidemiology of allergic drug reactions is poorly understood due, in large part, to difficulty in identifying true cases in population data sets. Use of International Classification of Diseases, Ninth Revision, Clinical Modification ( ICD-9-CM ) codes is a potentially valuable approach that requires formal evaluation. Objective To better understand the utility of ICD-9-CM codes for identification of allergic drug reactions, including the validation of specific codes by chart review. Methods We reviewed randomly sampled medical records of patients treated in the emergency department (ED) between January 1, 2001, and December 31, 2006, with ICD-9-CM codes for drug allergy and E codes (E930-949) for adverse drug reactions. Results During the 6-year period, 11,130 charts were identified by ICD-9-CM and E codes and 1,634 were reviewed. Allergic drug reactions were found in 444 (27%) of the reviewed ED visits. The codes that identified the highest percentage of true allergic drug reactions were dermatitis due to drug (693.0; 87%), adverse reaction to drug (995.2; 52%), and anaphylaxis (995.0; 38%). Patients with both an ICD-9-CM code and an E code had a high likelihood of having an allergic drug reaction (76%). Most allergic drug reactions were attributed to antibiotics (42%), intravenous contrast (7%), and nonsteroidal anti-inflammatory drugs (6%). The estimated frequency of allergic drug reactions increased from 0.49% of ED visits in 2001 to 0.94% in 2012. Conclusions Specific ICD-9-CM and E codes can be used in combination to identify allergic drug reactions. Further study of these codes in the inpatient and outpatient settings is necessary to better understand the utility of diagnosis codes for improving epidemiologic research on drug allergy.

Fas ligand (FasL) can be either membrane bound, or cleaved by metalloproteinases (MMP) to produce a soluble protein. The two different forms of FasL are reported to have opposite functions—membrane-bound FasL (mFasL) is proinflammatory and soluble FasL (sFasL) is antiinflammatory. We previously showed that, within the immune-privileged eye, tumors expressing high levels of mFasL overcame the suppressive ocular environment, triggered an inflammatory response, and were subsequently rejected. By contrast, eye tumors expressing low levels of mFasL grew progressively. To evaluate the effect of sFasL on the tumor growth and metastatic potential of ocular FasL-expressing tumors, we compared tumor cell clones that expressed equal amounts of (low) mFasL in the presence or absence of sFasL. Tumor cells transfected with a modified FasL gene expressed only mFasL (noncleavable), grew progressively within the eye, and induced systemic protective immunity that prevented metastatic spread of tumor cells to the liver. Unexpectedly, tumors transfected with wild-type FasL (wtFasL; cleavable), which could produce both sFasL and mFasL, elicited considerably more inflammation and grew more slowly within the eye. However, the cleavable wtFasL eye tumors failed to trigger protective immunity and gave rise to liver metastases. Interestingly, exposure to the ocular environment was required for the wtFasL tumors to gain metastatic potential. We conclude that the fate of FasL-expressing tumors is determined by a combination of the following: (a) the relative proportion of membrane and sFasL, and (b) the local environment that determines the extent of FasL cleavage. [Cancer Res 2007;67(24):11951–58]

A number of studies have documented a critical role for tumor-specific CD4+ cells in the augmentation of immunotherapeutic effector mechanisms. However, in the context of an extensive tumor burden, chronic stimulation of such CD4+ T cells often leads to the up-regulation of both Fas and Fas ligand, and coexpression of these molecules can potentially result in activation-induced cell death and the subsequent loss of effector activity. To evaluate the importance of T cell persistence in an experimental model of immunotherapy, we used DO11 Th1 cells from wild-type, Fas-deficient, and Fas ligand-deficient mice as effector populations specific for a model tumor Ag consisting of an OVA-derived transmembrane fusion protein. We found that the prolonged survival of Fas-deficient DO11 Th1 cells led to a more sustained tumor-specific response both in vitro and in vivo. Importantly, both Fas- and Fas ligand-deficient Th1 cells delayed tumor growth and cause regression of established tumors more effectively than wild-type Th1 cells, indicating that resistance to activation-induced cell death significantly enhances T cell effector activity.

It has been proposed that the constitutive expression of Fas ligand (FasL) in the eye maintains immune privilege, in part through inducing apoptosis of infiltrating Fas+ T cells. However, the role of FasL in immune privilege remains controversial due to studies that indicate FasL is both pro- and anti-inflammatory. To elucidate the mechanism(s) by which FasL regulates immune privilege, we used an ocular tumor model and examined the individual roles of the membrane-bound and soluble form of FasL in regulating ocular inflammation. Following injection into the privileged eye, tumors expressing only soluble FasL failed to trigger inflammation and grew progressively. By contrast, tumors expressing only membrane FasL 1) initiated vigorous neutrophil-mediated inflammation, 2) terminated immune privilege, and 3) were completely rejected. Moreover, the rejection coincided with activation of both innate and adaptive immunity. Interestingly, a higher threshold level of membrane FasL on tumors is required to initiate inflammation within the immune privileged eye, as compared with nonprivileged sites. The higher threshold is due to the suppressive microenvironment found within aqueous humor that blocks membrane FasL activation of neutrophils. However, aqueous humor is unable to completely block the proinflammatory effects of tumor cells that express high levels of membrane FasL. In conclusion, our data indicate that the function of FasL on intraocular tumors is determined by the microenvironment in conjunction with the form and level of FasL expressed.

Experimental and physiological expression of the pro-apoptotic molecule Fas-ligand can induce inflammation under certain conditions. Discussed here are the experimental situations, possible mechanisms, and pathways that mediate this response.

PURPOSE. Ocular immune privilege promotes tumor growth by hindering the development of innate and adaptive immunity. A prior study showed that ocular tumors expressing the membrane-only form of Fas ligand (FasL) terminate immune privilege, induce vigorous inflammation, undergo rejection, and induce systemic protective immunity. In these previous experiments the tumor cells used were genetically engineered to express membrane FasL. As an initial step toward developing an immunotherapy for intraocular tumors, the present study was conducted to examine whether injection of microvesicles expressing membrane FasL into ocular tumors (that are FasL negative) would have a similar effect. METHODS. Microvesicles expressing either no FasL or membrane-only Fas ligand were coinjected with L5178Y-R lymphoma cells into the anterior chambers (AC) of DBA/2 mice. RESULTS. Tumor cells coinjected with control vesicles grew progressively in the AC, and all mice died of metastatic disease by day 15. By contrast, a single injection of membrane FasL vesicles induced a potent inflammatory response characterized by GR1 + neutrophils and F4/80 + macrophages and significantly improved survival from 0% in untreated mice to 58% in mFasL-treated mice. Among the surviving mice, the ocular tumor was eliminated in 55%, and the mice exhibited systemic protection from a second tumor challenge. In the remaining 45%, the ocular tumor was not eliminated, but the mice were protected from liver metastases. CONCLUSIONS. Bioactive membrane FasL microvesicles coinjected with tumor cells induce a potent inflammatory response that terminates immune privilege, eliminates ocular tumors, and prevents metastatic disease.