Investigating the TNP‐OVA and direct popliteal lymph node assays for the detection of immunostimulation by drugs associated with anaphylaxis in humans

Gutting, Bradford W.; Updyke, Lawrence W.; Amacher, David E.

doi:10.1002/jat.847

Cited by 10 publications

(6 citation statements)

References 34 publications

(53 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We and others have previously shown that up-regulation of costimulatory signals, collectively representing signal 2, is a key process in drug-induced immune responses (Pieters & Albers 1999;Pirmohamed et al 2002;Seguin & Uetrecht 2003;Kaplowitz 2005;Nierkens et al 2005a, b;Uetrecht 2008). To demonstrate the capacity of a drug to provide co-stimulatory adjuvant signals, the potential to stimulate adaptive immune responses to unrelated bystander antigens, such as trinitrophenyl-ovalbumin (TNP-OVA), can be determined (Albers et al 1997;Gutting et al 1999Gutting et al , 2002Nierkens et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Oral exposure to immunostimulating drugs results in early changes in innate immune parameters in the spleen

Kwast

Fiechter

Kruijssen

et al. 2016

Journal of Immunotoxicology

View full text Add to dashboard Cite

The development of immune-dependent drug hypersensitivity reactions (IDHR) is likely to involve activation of the innate immune system to stimulate neo-antigen specific T-cells. Previously it has been shown that, upon oral exposure to several drugs with immune-adjuvant capacity, mice developed T-cell-dependent responses to TNP-OVA. These results were indicative of the adjuvant potential of these drugs. The present study set out to evaluate the nature of this adjuvant potential by focusing on early immune changes in the spleen, by testing several drugs in the same experimental model. Mice were exposed to one or multiple oral doses of previously-tested drugs: the non-steroidal-anti-inflammatory drug (NSAID) diclofenac (DF), the analgesic acetaminophen (APAP), the anti-epileptic drug carbamazepine (CMZ) or the antibiotic ofloxacin (OFLX). Within 24 h after the final dosing, early innate and also adaptive immune parameters in the spleen were examined. In addition, liver tissue was also evaluated for damage. Exposure to APAP resulted in severe liver damage, increased levels of serum alanine aminotransferase (ALT) and local MIP-2 expression. DF exposure did not cause visible liver damage, but did increase liver weight. DF also elicited clear effects on splenic innate and adaptive immune cells, i.e. increased levels of NK cells and memory T-cells. Furthermore, an increase in plasma MIP-2 levels combined with an influx of neutrophils into the spleen was observed. OFLX and CMZ exposure resulted in increased liver weights, MIP-2 expression and up-regulation of co-stimulatory molecules on antigen-presenting cells (APC). The data suggested that multiple immune parameters were altered upon exposure to drugs known to elicit immunosensitization and that broad evaluation of immune changes in straightforward short-term animal models is needed to determine whether a drug may harbor the hazard to induce IDHR. The oral exposure approach as used here may be applied in the future as an immunotoxicological research tool in this type of evaluation. ARTICLE HISTORY

show abstract

Section: Introductionmentioning

confidence: 99%

Oral exposure to immunostimulating drugs results in early changes in innate immune parameters in the spleen

Kwast

Fiechter

Kruijssen

et al. 2016

Journal of Immunotoxicology

View full text Add to dashboard Cite

show abstract

“…Streptozocin was shown to induce an IgG 2a or IgG 2b response with IFN-γ release due to stimulation of CD4 + T H1 cells, whereas diclofenac, zomepirac and glafenin induced an IgG 1 or IgE response due to T H2 stimulation and IL-4 release (Gutting et al, 2002a). Mercuric chloride as well as high doses of zomepirac and glafenin, however, produced a mixed IgG 1 , IgE, IgG 2a and IgG 2b response in this system (Albers et al, 1998;Gutting et al, 2002b).…”

Section: Modified Plnamentioning

confidence: 95%

Popliteal lymph node assay: facts and perspectives

Ravel¹,

Descotes²

2005

J. Appl. Toxicol.

View full text Add to dashboard Cite

The popliteal lymph node assay (PLNA) derives from the hypothesis that some supposedly immune-mediated adverse effects induced by certain pharmaceuticals involve a mechanism resembling a graft-versus-host reaction. The injection of many but not all of these compounds into the footpad of mice or rats produces an increase in the weight and/or cellularity of the popliteal lymph node in the treated limb (direct PLNA). Some of the compounds known to cause these adverse effects in humans, however, failed to induce a positive PLNA response, leading to refinements of the technique to include pretreatment with enzyme inducers, depletion of CD4(+) T cells or additional endpoints such as histological examination, lymphocyte subset analysis and cytokine fingerprinting. Alternative approaches have been used to improve further the predictability of the assay. In the secondary PLNA, the test compound is injected twice in order to illicit a greater secondary response, thus suggesting a memory-specific T cell response. In the adoptive PLNA, popliteal lymph node cells from treated mice are injected into the footpad of naive mice; a marked response to a subsequent footpad challenge demonstrates the involvement of T cells. Finally, the reporter antigens TNP-Ficoll and TNP-ovalbumin are used to differentiate compounds that induce responses involving neo-antigen help or co-stimulatory signals (modified PLNA). The PLNA is increasingly considered as a tool for detection of the potential to induce both sensitization and autoimmune reactions. A major current limitation is validation. A small inter-laboratory validation study of the direct PLNA found consistent results. No such study has been performed using an alternative protocol. Other issues include selection of the optimal protocol for an improved prediction of sensitization vs autoimmunity, and the elimination of false-positive responses due to primary irritation. Finally, a better understanding of underlying mechanisms is essential to determine the most relevant endpoints. The confusion resulting from use of the PLNA to predict autoimmune-like reactions as well as sensitization should be clarified. Interestingly, most drugs that were positive in the direct PLNA are also known to cause drug hypersensitivity syndrome in treated patients. This observation is expected to open new avenues of research.

show abstract

“…The parameters used-PLN size, weight, cellularity, and lymphocyte proliferation-are indicative for immunostimulation. The introduction of reporter antigen (RA) additionally makes it possible to differentiate between sensitizing drugs, nonsensitizing drugs with adjuvant activity, and "innocent" drugs (drugs with no detectable immunomodulatory activity; Albers et al, 1997;Gutting et al, 1999Gutting et al, , 2002 by means of the specific immunological requirements for obtaining an IgG antibody response to the RA.…”

Section: Background Informationmentioning

confidence: 99%

“…In summary, the specific requirements for obtaining an IgG antibody response to TNP-OVA or TNP-Ficoll make it possible to differentiate between sensitizing chemicals, chemicals that are nonsensitizing but which possess adjuvant activity, and innocent chemicals (Albers et al, 1997;Gutting et al, 1999Gutting et al, , 2002.…”

Section: Background Informationmentioning

confidence: 99%

The Reporter Antigen Popliteal Lymph Node Assay

Nierkens

Pieters

2006

CP Toxicology

View full text Add to dashboard Cite

Many chemicals, including drugs and environmental pollutants, may have the intrinsic capacity to stimulate or dysregulate immune responses. These responses may create considerable problems for exposed subjects in terms of development of autoimmunity or hypersensitivity reactions. The popliteal lymph node assay (PLNA) provides a suitable tool to assess the immunostimulating potential of chemicals and might be a potential candidate as a screening tool in immunotoxicological hazard identification. The use of so-called reporter antigens (RA) in this assay additionally enables differentiation between immunosensitizing (sensitizers), immunostimulating (irritants), and innocent chemicals. In the RA-PLNA, the compound of interest is injected into the hind footpad together with a nonsensitizing dose of the RA. After 6 to 8 days, RA-specific responses are monitored in the draining PLN by measuring RA-specific antibody formation, cytokine secretion, and shifts in immune cell numbers. Hence, this simple and straightforward assay provides immunologically relevant information about the immunomodulating properties of a chemical.

show abstract

Investigating the TNP‐OVA and direct popliteal lymph node assays for the detection of immunostimulation by drugs associated with anaphylaxis in humans

Cited by 10 publications

References 34 publications

Oral exposure to immunostimulating drugs results in early changes in innate immune parameters in the spleen

Oral exposure to immunostimulating drugs results in early changes in innate immune parameters in the spleen

Popliteal lymph node assay: facts and perspectives

The Reporter Antigen Popliteal Lymph Node Assay

Contact Info

Product

Resources

About