Regulatory T cells in allergy and asthma

Allergic diseases including asthma have risen considerably in prevalence in the last 50 years. A concomitant rise in autoimmune disease suggests a defect in immunoregulation, rather than a reduction in T-helper type 1 immunity. Immune responses to innocuous environmental antigens in health are characterized by dominant regulation through the production of interleukin-10 and transforming growth factor-beta. Recent studies suggest that diverse populations of regulatory T cells (Treg) play an important role in regulating T-helper type 2 (Th2) responses to allergens, maintaining functional tolerance. Regulatory responses appear to be compromised in allergic individuals but may be reconstituted to some extent with specific allergen immunotherapy. In experimental models, Treg can suppress Th2 responses to allergen, airway eosinophilia, mucous hypersecretion, and airway hyperresponsiveness. Further studies are required to precisely define the mechanisms of development and action of these cells, and to identify and evaluate novel targets for the treatment of allergic diseases.     

Interleukin-10-Secreting regulatory T cells in allergy and asthma

Allergic diseases, including asthma, are chronic inflammatory disorders originating from an aberrant immune response to innocuous antigens in our environment (allergens). In susceptible individuals, sensitization to allergen leads to the induction of allergen-specific Thelper type 2 (Th2) responses and immunoglobulin E (IgE) production. Subsequent challenge with allergen results in IgE-mediated mast cell activation and the recruitment and activation of effector cells, leading to clinical symptoms of disease. In this review, we discuss evidence that the anti-inflammatory cytokine interleukin-10 (IL-10) offers therapeutic promise for the control of asthma and allergy. We highlight the potential role of IL-10 secretion by a specialized T-cell subset, T regulatory cells, to prevent allergic inflammation in healthy individuals and to provide long-term relief from disease symptoms in allergic patients.     

The role of T cells in drug reaction

T cells are major protagonists of immune-mediated adverse drug eruptions. Immunohistochemical observation as well as isolation and functional characterization of T cells in.ltrating the affected tissues provided new insights into the pathomechanisms of the diverse clinical manifestations of drug hypersensitivity, and permitted the recognition of T cell-mediated cytotoxicity against drug-loaded resident cells as a major mechanism of tissue damage.     

Immune mechanisms in drug allergy.

Clinicians had suspected for years that drug eruptions were probably mediated by immune mechanisms because their timing suggested sensitization and specific immunologic memory rather than direct toxicity. An immune response to medications was also demonstrated by positive skin tests and by several types of in vitro tests that evidenced immediate or delayed hypersensitivity. In the last decade several teams of researchers obtained in vitro drug-specific human T-cell clones, in a variety of clinical types of drug eruptions. These clones were produced from blood or skin mononuclear cells of patients with a history of drug reaction by stimulation in vitro with drug. They were either of CD4 or CD8 phenotypes. Drug specific clones were stimulated by the parent drug much more often than by reactive metabolites. That challenged the classical "hapten hypothesis" that the immune response was initiated by reactive metabolites combined to self proteins. The medication usually stimulated specific T-cells after non-covalent binding to major histocompatibility (MHC) molecules on antigen presenting cells. In toxic epidermal necrolysis, T-lymphocytes present at the site of lesions, exhibited a drug specific cytotoxicity against autologous target cells, or allogeneic cells that shared the same HLA than autologous cells. This MHC class I restriction and mediation of death by perforin/granzyme release, is the classical behavior of cytotoxic T lymphocytes, like those operating in the reject of a transplanted organ. MHC restriction could explain the key role of HLA genes as predisposing factors to severe drug reactions. A strong association between HLA and hypersensitivity to abacavir, SJS or TEN to carbamazepine or allopurinol has been recently demonstrated. Resemblance to graft rejection points to the possible therapeution value of immuno suppressive agents. Most drug eruptions appear to result from T-cell mediated delayed hypersensitivity. The secondary activation of different cascades of cytokines, may contribute to the heterogeneity of clinical presentations.     

Desensitization in patients with beta-lactam drug allergy

BackgroundPatients with a history of beta-lactam antibiotic allergy are often admitted to the hospital with severe or life-threatening infections requiring beta-lactam antibiotics. Strict avoidance of beta lactams to such patients may prevent them from getting adequate coverage and can lead to an increase in the use of alternative antibiotics, which can predispose to antibiotic resistance. Past studies revealed a lower incidence of pen allergy then patients’ histories suggest. Fortunately today, there are three options for patients presenting with a history of beta-lactam allergy. Penicillin skin testing, beta-lactam challenge or beta-lactam desensitization.Recently Pre Pen has been FDA re-approved and when combined with Pen G is a valid way to determine if patients are able to tolerate beta-lactam antibiotic. When these agents are not available one must decide about desensitization or challenge. When a patient has a positive penicillin skin test, desensitization or beta-lactam avoidance are the only options.This paper reviews the safety of beta-lactam desensitization.ObjectiveTo perform a chart review on patients desensitised with beta lactam to determine if desensitizations can be performed safely without minimal complications.MethodsA retrospective chart review was performed on allergy and immunology inpatient consultations for beta-lactam desensitization between September 2003 and August 2006 at the Cedars-Sinai Medical Centre in Los Angeles. Patient data and outcomes of desensitization were analysed.ResultsA total of 13 intravenous desensitizations were performed on 12 patients. The patients consisted of eight females and four males with an average age of 65 years. Age range was 36–92 years old. All 13 intravenous desensitizations were completed without complications. No patient required a slower rate of desensitization or discontinuance of the desensitization. Patients were able to tolerate the initial therapeutic dose of their beta-lactam antibiotic and were then able to complete full therapeutic courses of their antibiotic.ConclusionBeta-lactam antibiotic sensitivity continues to present a challenging problem for physicians. Patients with drug resistant infections who are unable to obtain skin testing or who test positive to skin tests may need either a challenge or desensitization. Desensitization, saved for those with a convincing beta-lactam hypersensitivity history is often the choice of last resort given the associated cost and risk of anaphylaxis. However, once desensitization is complete, patients are usually able to tolerate full doses of antibiotics for full treatment length with minimal side effects.     

Epithelial cells in ocular allergy

Conjunctival epithelial cells do not act only as mechanical barriers, preventing the entry of particles, bacteria, viruses, and noxious substances into the eye but they are also active participants in the regulation of allergic inflammation via expressing adhesion/effector molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, human leukocyte antigen-DR, CD40/CD40L, Fas/Fas ligand) on their surfaces and releasing numerous proinflammatory cytokines, such as eotaxin, regulated on activation normal T-cell expressed and released (RANTES), macrophage inflammatory protein-1, interleukin (IL)-8, IL-6, and tumor necrosis factor-á, which are necessary for the proliferation, differentiation, activation, and chemotaxis of various inflammatory cells into the conjunctiva. Histamine, released from the conjunctival mast cells, might stimulate the synthesis of proinflammatory molecules such as IL-6 and IL-8 by the epithelial cells through the receptors that couple to inositol phosphate generation and, therefore, amplify the allergic response. The relationship between the epithelium and allergy should be considered in detail in future studies aiming at an effective control and treatment of all forms of allergic conjunctivitis.     

Prevalence of drug allergy in an out-patient population

The prevalence of drug allergy in an out-patient population has been studied, 448 cases were diagnosed mainly to NSAIDS and beta-lactams and local anesthetics, sulfa drugs, quinolones and others. Clinical history and skin tests are sufficient to diagnose most cases of drug allergy.     

The problem of drug allergy in patients with tuberculosis

Some aspects of drug allergy in tuberculosis patients are given. The rate of drug allergy in these cases makes up 14.65% and tends to further increase. The frequency of such allergy depends on sex, age, specificity of a tuberculous process and underlying diseases. A list of the drugs more frequently causing allergic reactions was made. As far as antituberculosis institutions are concerned, it seems necessary to organize proper prevention, diagnosis and treatment of drug allergies that would meet modern requirements.     

Dendritic cells: importance in allergy.

In this review we discuss the role of dendritic cells (DC) in the pathogenesis of allergic contact hypersensitivity (ACH) and atopic disorders, such as asthma and atopic eczema. In ACH patients, DC recognize the invasion of simple chemicals such as haptens, and trigger antigen-specific T cell responses leading to the characteristic histological and clinical changes such as spongiosis and papulovesicular eruptions. During atopic disorders, it is well known that the Th2-deviated immune response plays a crucial role in their pathogenesis. DC provide T cells with antigen and costimulatory signals (signals 1 and 2, respectively), as well as with a polarizing signal (signal 3). When studying ACH, it is important to understand how simple chemicals induce the activation of DC and their migration to the draining lymph nodes where they supply signals 1 and 2 to naive T cells. The mechanisms by which DC induce the Th2-deviated immune response, namely via the Th2-deviated signal 3, are central topics in the pathogenesis of atopic disorders.     

Children with untreated food allergy express a relative increment in the density of duodenal gammadelta+ T cells

BACKGROUND: We investigated whether children with food allergy (FA) express increased densities of intraepithelial gammadelta+ T cells similarly to subjects with celiac disease. METHODS: The duodenal specimens taken by gastroduodenoscopy from 20 children with untreated FA, 17 with treated FA, 12 with celiac disease (CD) and 12 controls were studied with monoclonal antibodies and a three-layer peroxidase staining method. RESULTS: The subjects with untreated FA expressed equal densities of total intraepithelial CD3+ and alpha/beta+ T cells, but significantly higher densities of gammadelta+ cells than the subjects currently on an elimination diet for FA or the controls. Accordingly, their gammadelta+/CD3+ ratio was higher. On the other hand, the results differed clearly from CD, where all the three cell populations showed high densities. Another finding that discriminated the subjects with FA from the CD patients was endoscopic examination. Lymphonodular hyperplasia (LNH) of the duodenal bulb with a normal villous pattern was demonstrated in 14 (70%) of the 20 subjects with untreated FA and in 8 (47%) of the 17 with treated FA, but in none of the celiac patients or controls. Surprisingly, the biopsy samples from the subjects with FA showed quite normal histological findings. CONCLUSIONS: According to this preliminary observation, high densities of intraepithelial gammadelta+ T cells and a significantly elevated gammadelta+/CD3+ ratio are associated with untreated FA. If seen LNH in a gastroduodenoscopy and/or increased densities of gammadelta+ T cells in the biopsy specimen, the possibility of gastrointestinal FA should be reliably assessed by a food challenge.     

Immunomodulatory drug costimulates T cells via the B7-CD28 pathway

Although thalidomide (Thal) does not directly induce T-cell activation, it increases proliferation of T cells following CD3 activation. In this study, we examined the immunomodulatory effects of a more potent analog of Thal, immunomodulatory drug (IMiD), on T cells. Although IMiD3 does not directly stimulate proliferation of normal donor CD3+ T cells, it significantly costimulates proliferation of CD3+ T cells induced by CD3 ligation (stimulation index [SI], 2.4), immature dendritic cells (DCs; SI, 2.1), and mature DCs (SI, 2.6). T-cell proliferation triggered by DCs was abrogated by cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA-4-Ig), and IMiD3 partially overcomes this inhibitory effect. IMiD3 also overcomes the inhibitory effects of CTLA-4-Ig on Epstein-Barr virus (EBV) and influenza (Flu)-specific CD4 and CD8 T-cell responses, as measured by cytokine capture and enzyme-linked immunosorbent spot (ELISPOT) assay. IMiD3 did not induce up-regulation of CD28 expression on T cells, or of CD80-CD86 expression on dendritic cells. Importantly, IMiD3 triggers tyrosine phosphorylation of CD28 on T cells, followed by activation of nuclear factor kappaB (NF-kappaB), a known downstream target of CD28 signaling. These results therefore define the costimulatory mechanism whereby IMiD3 induces T-cell activation and provide the cellular and molecular basis for use of IMiD3 as an adjuvant in immunotherapeutic treatment strategies for multiple myeloma.     

Immune dysfunction in chronic lymphocytic leukemia T cells and lenalidomide as an immunomodulatory drug

A new agent that is being used in chronic lymphocytic leukemia (CLL) and is receiving considerable interest is the immunomodulatory drug lenalidomide. The precise anti-CLL mechanism of action of lenalidomide is not yet completely defined. In this perspective article, Drs. Ramsay and Gribben examine the multiple biological effects of lenalidomide on various cell targets that likely contribute to its anti-CLL activity. See related paper on page 1266.Developing more effective therapeutic options and treatment regimes for patients with chronic lymphocytic leukemia (CLL) is the subject of on going international clinical studies involving chemo-immunotherapy approaches that incorporate monoclonal antibodies such as rituximab (anti-CD20). Results have demonstrated remarkably improved clinical response rates for CLL patients receiving such treatment regimes.¹ To aid the pursuit of curative treatment strategies, particularly for relapsed patients who are unlikely to respond to standard approaches, novel agents for CLL are required. Immune therapy represents a promising treatment approach,² as demonstrated by the improved results in CLL with chemo-immunotherapy and successful demonstration of a graft-versus-leukemia effect after allogeneic stem cell transplantation leading to long-term clinical remissions.³ However, CLL is associated with immune dysfunction and it is becoming increasingly clear that CLL tumor cells co-opt immunosuppressive mechanisms to evade immune recognition. For example, although CLL cells express tumor antigens that can be presented by major histocompatibility complex (MHC) class I and class II molecules, an effective immune response is not elicited against the tumor cells.^4,5 This likely contributes to the clinical pattern of a progressively growing tumor population over time. The failure to mount an effective immune response can be explained, in part, by a lack of effective antigen presentation, as manifested by low levels of expression of adhesion and co-stimulatory molecules essential for the induction of effective immune responses. In addition, CLL cells are known to secrete immunosuppressive cytokines such as interleukin (IL)-6 and IL-10. Thus, repairing the immune dysfunction in CLL is an essential step in order to harness and promote immune cell-mediated anti-cancer responses.A new agent that is being used in CLL and is receiving considerable interest is the second- generation immunomodulatory drug, lenalidomide (Revlimid; Celgene). Lenalidomide is designed to enhance the immunological and anti-cancer properties of its parent drug thalidomide, while attenuating neurotoxic adverse reactions. Lenalidomide has been shown to be clinically effective as a single agent in relapsed and refractory CLL patients,^6,7 and ongoing clinical trials are also assessing its efficacy in previously untreated patients. The precise anti-CLL mechanism of action of lenalidomide is not yet completely defined. Potential mechanisms of action include blockade of angiogenesis and pro-tumor cytokines, inhibition of stromal cell-CLL cell interactions, and enhancement of immune cell function including that of T cells, monocytes and NK cells. Of note, in contrast to lenalidomide’s anti-tumor activity in multiple myeloma, no direct in vitro pro-apoptotic effect of lenalidomide has been observed using primary CLL cells.⁸Uniquely in CLL, the use of lenalidomide is associated with a tumor flare reaction that has been postulated to be associated with a drug-induced, immune-mediated anti-tumor response. This tumor flare reaction is manifested as an acute onset of swelling of involved lymph nodes with inflammation of the overlying skin, rash and fever. Aue et al., in a study published in this issue of the Journal,⁹ show that when relapsed patients are treated with lenalidomide this flare reaction is associated with induction of CLL cell co-stimulatory molecules and T-cell activation. Their findings highlight the need to combine the current understanding of CLL biology, including immune dysfunction, with the results of correlative functional studies in order to identify the critical mechanisms of action of lenalidomide as a new agent in CLL.