Presentation is loading. Please wait.

Presentation is loading. Please wait.

Targeting Effector Memory T Cells with the Small Molecule Kv1

Published byDonato Valentini Modified over 5 years ago

Similar presentations

Presentation on theme: "Targeting Effector Memory T Cells with the Small Molecule Kv1"— Presentation transcript:

1 Targeting Effector Memory T Cells with the Small Molecule Kv1
Targeting Effector Memory T Cells with the Small Molecule Kv1.3 Blocker PAP-1 Suppresses Allergic Contact Dermatitis  Philippe Azam, Ananthakrishnan Sankaranarayanan, Daniel Homerick, Stephen Griffey, Heike Wulff  Journal of Investigative Dermatology  Volume 127, Issue 6, Pages (June 2007) DOI: /sj.jid Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

2 Figure 1 Ear infiltrating cells in ACD are CD8+, CD45RC−, and Kv1.3+. (a, c, and e) Consecutive slides from a vehicle-treated rat ear, whereas (b, d, and f) are pictures of consecutive slides from an oxazolone challenged ear. (a and b) Stained for CD8, (c and d) for CD45RC, and (e and f) for Kv1.3. Bar=200μm. Journal of Investigative Dermatology  , DOI: ( /sj.jid ) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

3 Figure 2 Pharmacokinetics of PAP-1. (a) Total PAP-1 plasma concentrations in Lewis rats (n=3) following intravenous injection at 6mg/kg. The data were fitted as a second-order exponential decay for a two-compartment model with Winnonlin® software (y=A × exp−αxt+B × exp−βxt where A=9.58±0.72, B=2.00±0.16, α=3.18±0.33hours−1 and β=0.23±0.01hours−1; K10=0.99±0.06hours−1, K12=1.68±0.23hours−1, and K21=0.74±0.09hours−1; steady-state volume of distribution Vss=1.6±0.06l/kg. (b) Total PAP-1 plasma concentrations following i.p. injection at 1 (•), 6 (○), or 10 (▴) mg/kg (n=3 for each concentration). All values are given as the mean±SEM of total PAP-1 concentrations. Journal of Investigative Dermatology  , DOI: ( /sj.jid ) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

4 Figure 3 PAP-1 inhibits the elicitation phase of ACD when administered i.p., orally, or topically. (a) Rats were treated i.p. with the vehicle Cremophor®EL/PBS (n=30), PAP-1 at 1mg/kg (n=9, 71.5±3.3% of control, P=0.002), 6mg/kg (n=20, 43.5±4.8% of control, P= ), 10mg/kg (n=16, 42.0±5.4% of control, P= ), or with ShK at 16μg/kg (n=3, 31.8±14.9% of control, P= vs control and P=0.45 vs 10mg/kg PAP-1). (b) Rats were gavaged with the vehicle peanut oil (n=5) PAP-1 at 5mg/kg (n=5, 77.2±5.0% of control, P=0.037), 20mg/kg (n=5, 69.5±13.3% of control, P=0.081) or 50mg/kg (n=5, 48.4±8.2% of control, P=0.002). (c) Rats were treated topically on the ears with 50μl of the vehicle acetone:DMSO (n=10), PAP-1 at 10mg/ml (n=10, 45.1±6.1% of control, P=0.0002) or AS-85 at 10mg/ml (n=9, 68.9±8.2% of control, P=0.03). (d) PAP-1 was applied as a 2% cream in DermabaseTM (n=7, 79.8±15.4% of control, P=0.15) or Eucerin® (n=8, 37.2±4.8% of control, P= ). The controls (n=14) were treated either with “empty” DermabaseTM (n=7) or Eucerin® (n=7) and the results (181μm swelling) averaged as there was no significant difference between the two vehicles. Values are given as the mean±SEM of swelling in percent. The average ear swelling in all controls from all conditions was 168.5μm. Journal of Investigative Dermatology  , DOI: ( /sj.jid ) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

5 Figure 4 PAP-1 suppresses oxazolone-induced inflammation by reducing CD8+ T cells infiltration and production of the inflammatory cytokines IFN-γ and IL-17 but not TNF-α. Ears were removed 24hours after the challenge from (a) vehicle or (b) PAP-1-treated rats and stained for CD8+ T cells. Bar=200μm. (c and d) mRNA quantities measured for (c) CD8-β, Kv1.3, IL-17, IL-2, and TNF-α or (d) IFN-γ from vehicle (filled black bars) or PAP-1-(10mg/kg, diagonal strips) treated rats. Six unchallenged ears were used as calibrator. Results are expressed as induction factors against the calibrator±SEM (n=10 ears). Journal of Investigative Dermatology  , DOI: ( /sj.jid ) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

6 Figure 5 PAP-1 does not prevent sensitization or TPA-induced inflammation. (a) PAP-1 does not prevent sensitization for ACD. Rats were injected i.p. with the vehicle Cremophor®EL/PBS (n=8) or with PAP-1 at 10mg/kg (n=8) twice daily starting 2 days before sensitization with 1% oxazolone and for 3 days after sensitization. Animals were challenged with 0.2% oxazolone 7 days after sensitization. (b) PAP-1 does not suppress TPA-induced irritation. Rats were treated with 5μg of TPA in 100μl of AOO (4:1) on each side of both ears and injected i.p. with the vehicle Cremophor®EL/PBS (n=4) or with PAP-1 at 10mg/kg (n=4) at 8-hour intervals starting 20hours before and for 20hours after TPA treatment. Both ears were measured. The average ear swelling in TPA controls was 110.8μm. Values are given as the mean±SEM of swelling in percent. Journal of Investigative Dermatology  , DOI: ( /sj.jid ) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

7 Figure 6 PAP-1 is not a contact sensitizer according to the LLNA IL-2 method. Vehicle (AOO), Triton®X mg/ml, oxazolone 0.2mg/ml, or PAP-1 at 10, 25, or 50mg/ml were applied to mouse ears daily for 3 consecutive days. Two days later, lymph node cells from the draining lymph nodes were collected and cultured for 15hours in the presence of 10μg/ml PHA-P and IL-2 concentrations in culture supernatant measured by ELISA. Values are given as stimulation index, which is the ratio of IL-2 released by lymph node cells from compound-treated animals to IL-2 released by lymph node cells from vehicle-treated animals. Values are given as the average of two independent experiments with four mice per group±SEM. Journal of Investigative Dermatology  , DOI: ( /sj.jid ) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

8 Figure 7 PAP-1 is not a contact sensitizer in vitro. (a) MUTZ-3 and (b) THP-1 myeloid cell lines were cultured for 24hours in the presence of vehicle (DMSO), the irritant SDS at 200μm, the sensitizer dinitrochlorobenzene at 3.75μm or PAP-1 at 10, 20, or 40μm. CD86 expression was then measured by flow cytometry. Values are given as a stimulation index (SI), which is the ratio of CD86 expression of treated cells over CD86 expression of DMSO-treated cells (SI=(% of cells expressing CD86+ × mean fluorescence intensity of CD86+ cells) of treated/(% of cells expressing CD86+ × mean fluorescence intensity of CD86+ cells) of control). The values are the average±SEM of two independent experiments. Journal of Investigative Dermatology  , DOI: ( /sj.jid ) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

Download ppt "Targeting Effector Memory T Cells with the Small Molecule Kv1"

Similar presentations

Hesperidin ameliorates immunological outcome and reduces neuroinflammation in the mouse model of multiple sclerosis  Dariush Haghmorad, Mohammad Bagher.

Hesperidin ameliorates immunological outcome and reduces neuroinflammation in the mouse model of multiple sclerosis  Dariush Haghmorad, Mohammad Bagher.
FK506 Controls CD40L-Induced Systemic Autoimmunity in Mice

FK506 Controls CD40L-Induced Systemic Autoimmunity in Mice
Topical Application of A Novel Immunomodulatory Peptide, RDP58, Reduces Skin Inflammation in the Phorbol Ester-Induced Dermatitis Model  Christopher G.

Topical Application of A Novel Immunomodulatory Peptide, RDP58, Reduces Skin Inflammation in the Phorbol Ester-Induced Dermatitis Model  Christopher G.
Therapeutic Potential of B and T Lymphocyte Attenuator Expressed on CD8+ T Cells for Contact Hypersensitivity  Daiki Nakagomi, Kotaro Suzuki, Junichi.

Therapeutic Potential of B and T Lymphocyte Attenuator Expressed on CD8+ T Cells for Contact Hypersensitivity  Daiki Nakagomi, Kotaro Suzuki, Junichi.
Glutamine Suppresses DNFB-Induced Contact Dermatitis by Deactivating p38 Mitogen– Activated Protein Kinase via Induction of MAPK Phosphatase-1  Otgonzaya.

Glutamine Suppresses DNFB-Induced Contact Dermatitis by Deactivating p38 Mitogen– Activated Protein Kinase via Induction of MAPK Phosphatase-1  Otgonzaya.
Peptide Immunization Indicates that CD8+ T Cells are the Dominant Effector Cells in Trinitrophenyl-Specific Contact Hypersensitivity  Stefan Martin, Michael.

Peptide Immunization Indicates that CD8+ T Cells are the Dominant Effector Cells in Trinitrophenyl-Specific Contact Hypersensitivity  Stefan Martin, Michael.
Tatsukuni Ohno, Yuta Kondo, Chenyang Zhang, Siwen Kang, Miyuki Azuma 

Tatsukuni Ohno, Yuta Kondo, Chenyang Zhang, Siwen Kang, Miyuki Azuma 
The Protective Effects of Melittin on Propionibacterium acnes–Induced Inflammatory Responses In Vitro and In Vivo  Woo-Ram Lee, Kyung-Hyun Kim, Hyun-Jin.

The Protective Effects of Melittin on Propionibacterium acnes–Induced Inflammatory Responses In Vitro and In Vivo  Woo-Ram Lee, Kyung-Hyun Kim, Hyun-Jin.
A Toll-Like Receptor 7, 8, and 9 Antagonist Inhibits Th1 and Th17 Responses and Inflammasome Activation in a Model of IL-23-Induced Psoriasis  Weiwen.

A Toll-Like Receptor 7, 8, and 9 Antagonist Inhibits Th1 and Th17 Responses and Inflammasome Activation in a Model of IL-23-Induced Psoriasis  Weiwen.
Topical ROR Inverse Agonists Suppress Inflammation in Mouse Models of Atopic Dermatitis and Acute Irritant Dermatitis  Jun Dai, Min-Kyung Choo, Jin Mo.

Topical ROR Inverse Agonists Suppress Inflammation in Mouse Models of Atopic Dermatitis and Acute Irritant Dermatitis  Jun Dai, Min-Kyung Choo, Jin Mo.
Trichomide A, a Natural Cyclodepsipeptide, Exerts Immunosuppressive Activity against Activated T Lymphocytes by Upregulating SHP2 Activation to Overcome.

Trichomide A, a Natural Cyclodepsipeptide, Exerts Immunosuppressive Activity against Activated T Lymphocytes by Upregulating SHP2 Activation to Overcome.
Antigen-Specific Peripheral Tolerance Induced by Topical Application of NF-κB Decoy Oligodeoxynucleotide  Iwao Isomura, Kunio Tsujimura, Akimichi Morita 

Antigen-Specific Peripheral Tolerance Induced by Topical Application of NF-κB Decoy Oligodeoxynucleotide  Iwao Isomura, Kunio Tsujimura, Akimichi Morita 
Absence of CCR4 Exacerbates Skin Inflammation in an Oxazolone-Induced Contact Hypersensitivity Model  Sari Lehtimäki, Sari Tillander, Anne Puustinen,

Absence of CCR4 Exacerbates Skin Inflammation in an Oxazolone-Induced Contact Hypersensitivity Model  Sari Lehtimäki, Sari Tillander, Anne Puustinen,
Α-MSH-Stimulated Tolerogenic Dendritic Cells Induce Functional Regulatory T Cells and Ameliorate Ongoing Skin Inflammation  Matteo Auriemma, Thomas Brzoska,

Α-MSH-Stimulated Tolerogenic Dendritic Cells Induce Functional Regulatory T Cells and Ameliorate Ongoing Skin Inflammation  Matteo Auriemma, Thomas Brzoska,
Aspartame Attenuates 2, 4-Dinitrofluorobenzene-Induced Atopic Dermatitis–Like Clinical Symptoms in NC/Nga Mice  Gun-Dong Kim, Yong Seek Park, Hyun-Jong.

Aspartame Attenuates 2, 4-Dinitrofluorobenzene-Induced Atopic Dermatitis–Like Clinical Symptoms in NC/Nga Mice  Gun-Dong Kim, Yong Seek Park, Hyun-Jong.
Topical Peroxisome Proliferator Activated Receptor-α Activators Reduce Inflammation in Irritant and Allergic Contact Dermatitis Models1  Mary Y. Sheu,

Topical Peroxisome Proliferator Activated Receptor-α Activators Reduce Inflammation in Irritant and Allergic Contact Dermatitis Models1  Mary Y. Sheu,
IL-23 from Langerhans Cells Is Required for the Development of Imiquimod-Induced Psoriasis-Like Dermatitis by Induction of IL-17A-Producing γδ T Cells 

IL-23 from Langerhans Cells Is Required for the Development of Imiquimod-Induced Psoriasis-Like Dermatitis by Induction of IL-17A-Producing γδ T Cells 
Th17 Cytokines Stimulate CCL20 Expression in Keratinocytes In Vitro and In Vivo: Implications for Psoriasis Pathogenesis  Erin G. Harper, Changsheng Guo,

Th17 Cytokines Stimulate CCL20 Expression in Keratinocytes In Vitro and In Vivo: Implications for Psoriasis Pathogenesis  Erin G. Harper, Changsheng Guo,
Langerhans Cells Are Required for UVR-Induced Immunosuppression

Langerhans Cells Are Required for UVR-Induced Immunosuppression
Mitigation of Delayed-Type Hypersensitivity Reactions by a CD44 Variant Isoform v3- Specific Antibody: Blockade of Leukocyte Egress  Simone Seiter, Peter.

Mitigation of Delayed-Type Hypersensitivity Reactions by a CD44 Variant Isoform v3- Specific Antibody: Blockade of Leukocyte Egress  Simone Seiter, Peter.

Similar presentations

Ads by Google