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233 Myeloid-derived suppressor cells (MDSC) in psoriasis are an expanded population with diverse T cell-suppressor mechanisms
Clinical Research II: Pathophysiology and Therapeutics | ABSTRACTS 228
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Skin directed immunotherapies increase tumor infiltrating lymphocytes in patients with cutaneous metastatic breast cancer JY Jung, Y Yuan, S Krishnasamy, T Almazan and J Mortimer City of Hope National Comprehensive Cancer Center, Duarte, CA Cutaneous metastases from breast cancer are common, occurring in 20-30% of patients with metastatic disease and is often the first site of disease recurrence. These metastases are often morbid, leading to significant pain, bleeding and psychological distress. Breast cancer is not considered a classically immunogenic tumor: incidence does not increase in immunosuppressed patients, spontaneous remission is very rare, and clinical trials of systemic immunotherapies such as anti-CTLA4 and anti-PD1 antibodies have shown poor or modest response rates. However, recent evidence suggests that pre-existing tumor infiltrating lymphocytes in breast cancer can predict overall survival and response to therapy. We hypothesized that skin directed therapies could increase the number of tumor infiltrating lymphocytes and ultimately lead to improved clinical response. Of 7 patients treated at our institution, average age was 55 (range 38 to 68 years old) and all had metastatic breast cancer with cutaneous involvement: 3 were ER/PR+, 2 were HER2+, and 2 were triple negative. Three patients received cryotherapy plus topical fluorouracil and 4 patients received a combination of cryotherapy, intra-lesional GM-CSF and imiquimod. Five of seven patients were treated with concurrent endocrine, targeted or chemotherapy. Biopsies available from 4 of the treated patients showed dramatic increases in the number of tumor infiltrating lymphocytes (up to 20 fold). Three patients had complete response in the skin including 2 of the patients (HER2+) demonstrated durable remission. An abscopal, or bystander effect, was noted in un-treated lesions, seen clinically and histologically as early as 2 weeks following treatment. We hypothesize that the skin directed therapies may create an in situ vaccination of the tumor thus enhancing tumor specific immune responses. Skin directed immunotherapies are easily administered, well tolerated and may improve clinical outcomes.
Recipient skin resident memory T cells can induce GvHD-like dermatitis in human engrafted mice TR Matos, KF Lima, A Gehad, CP Elco, EL Lowry, J Teague, S Divito, TS Kupper and R Clark Brigham and Women’s Hospital, Harvard Medical School, Boston, MA Graft-versus-Host-Disease (GvHD) is a major cause of illness and death in patients following hematopoietic stem cell transplantation (SCT). GvHD is assumed to result from donor-derived T cells attacking recipient tissues. However, GvHD is most common in the gut, liver and skin, tissues that contain large populations of long-lived resident memory T cells (TRM). We have found that skin resident T cells survive classic conditioning regimens including total body irradiation and alemtuzumab. We hypothesize that surviving recipient-derived skin resident T cells may contribute to GvHD by interacting with newly generated donor-derived APC that have migrated into skin. To test this hypothesis, we grafted immunodeficient NSG mice with adult human skin containing TRM and then infused them 3 weeks later with equivalent numbers of either allogeneic PBMC (T cells + APC) or monocytes alone (APC). Skin grafts were harvested 3 weeks later and studied by histology, TCR sequencing and RT-PCR. In mice injected with APC alone, the only source of T cells was those resident in the adult skin graft. Mice injected with APC had a GvHD-like dermatitis by histology (mean grade 1.5, vs. 0.25 for saline injected and 2.54 for PBMC injected mice) and had increased numbers of T cells in the skin graft compared to saline injected mice (p<0.01). TCR sequencing confirmed that T cell clones present in the skin before grafting expanded in the skin after exposure to allogeneic APC. Skin grafts from mice infused with APC alone vs. PBMC had similarly elevated levels of IL-17A and TNFa. IL-22 was significantly higher in APC injected mice and IFNg was higher in PBMC injected mice. In summary, interactions between skin resident T cells and infused APC induced T cell proliferation and production of cytokines known to participate in the pathogenesis of GvHD. Our studies support a possible role for TRM in GvHD and suggest that TRM depletion strategies may be helpful in reducing GvHD.
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A mild topical steroid leads to progressive anti-inflammatory effects in skin of moderate-tosevere atopic dermatitis PM Brunner1, S Khattri1,2, S Garcet1, R Finney3, M Oliva1,2, R Dutt1,2, J Fuentes-Duculan1, X Zheng1, X Li1, KM Bonifacio1, N Kunjravia1, I Coats1, I Cueto1, P Gilleaudeau1, M SullivanWhalen1, M Suarez-Farinas2,1, JG Krueger1 and E Guttman-Yassky2,1 1 The Rockefeller University, New York, NY, 2 Icahn School of Medicine at Mount Sinai, New York, NY and 3 Jefferson Medical College, Philadelphia, PA Background: Topical glucocorticosteroids (GCS) are considered an efficient treatment option for atopic dermatitis (AD), but a global assessment of GCS responses on key disease circuits upon weeks-to-months of treatment is currently lacking. Objective: To assess short (4wks) and long-term (16wks) application of topical GCS on AD skin, and define response biomarkers. Methods: Triamcinolone 0.025% cream effects were assessed by gene expression and IHC studies at baseline, 4wks, and 16wks in biopsies from 15 moderate-to-severe AD patients. Results: At 16wks, only 3 patients were clinical responders (using SCORAD50 criteria), but 6 patients qualified as responders based on histological criteria. Baseline characteristics indicated more severe disease in non-responders. While 3/15 patients experienced only transient benefit after 4wks, others showed progressive improvements towards 16wks. Topical GCS use in AD patients resulted in improvements of the AD genomic signature of 25.6% at 4wks and 71.8% at 16wks, respectively, and even 123.9% in the histological responder group. Cytokines (IL-12p40, IL-13, IL-22, CCL17, CCL18, PI3/elafin, S100As) showed consistent decreases from baseline towards 16wks with corresponding improvements in epidermal disease hallmarks (K16, loricrin) in lesional skin from responders (p<0.05). Non-responders largely showed lesser/non-significant reductions of these key inflammatory and barrier markers. The combination of IL-21 and IFN-g baseline expression closely predicted individual clinical GCS responses at 16wks of treatment. Conclusion: Even low-potency GCS can broadly affect immune and barrier responses in moderate-to-severe AD patients, associating higher baseline severity with increased steroid-resistance in AD patients.
Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis S Khattri1,2, PM Brunner1, S Garcet1, R Finney3, SR Cohen4, M Oliva1,2, R Dutt1,2, J FuentesDuculan1, X Zheng1, X Li1, KM Bonifacio1, N Kunjravia1, I Coats1, I Cueto1, P Gilleaudeau1, M Sullivan-Whalen1, M Suarez-Farinas2,1, JG Krueger1 and E Guttman-Yassky2,1 1 The Rockefeller University, New York, NY, 2 Icahn School of Medicine at Mount Sinai, New York, NY, 3 Jefferson Medical College, Philadelphia, PA and 4 Albert Einstein College of Medicine, New York, NY Background: Treatment options for moderate-to-severe atopic dermatitis (AD) are limited. Ustekinumab is an IL-12/IL-23p40 blocker that suppresses Th1, Th17 and Th22 activation, commonly used for psoriasis. Objective: To assess safety and efficacy of ustekinumab in moderate-to-severe AD. Methods: In this phase II, double-blind, placebo-controlled study, 33 patients with moderate-to-severe AD were randomly assigned to either ustekinumab (n¼16) or placebo (n¼17), with subsequent crossover at 16wks, and last dose at 32wks. Background therapy (mild topical steroids) was allowed to increase compliance. Study endpoints included clinical (SCORAD50) and biopsy-based measures of tissue structure and inflammation, using protein and gene expression studies. Results: The ustekinumab group achieved higher SCORAD50 responses at 12, 16 (primary endpoint), and 20wks than placebo, but the difference between groups was not significant. The AD molecular profile/transcriptome showed early robust gene modulation, with sustained further improvements until 40wks, only in the initial ustekinumab-group. Distinct and more robust modulation of Th1, Th17 and Th22 but also Th2-related AD genes was seen only after 4wks of ustekinumab treatment (i.e. MMP12, IL-22, IL-13, IFN-g, elafin/PI3, CXCL1, CCL17; p<0.05). Epidermal responses (K16, terminal differentiation) showed faster (4wks) and long-term regulation (32wks) from baseline in the ustekinumab-group. No severe adverse events were observed. Conclusions:Ustekinumab had clear and sustained clinical and molecular effects, but clinical outcomes might have been obscured by a profound “placebo” effect, most likely due to background topical steroids and possibly too extended treatment intervals.
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Immunohistochemical characterization of inflammatory discoid lupus erythematosus skin with and without dermal scarring JC O’Brien1, GA Hosler2 and B Chong1 1 Dermatology, University of Texas Southwestern Medical Center, Dallas, TX and 2 Propath Dermatopathology, Dallas, TX Discoid lupus erythematosus (DLE) skin predominantly contains CD4+ and CD8+ T cells, B cells, macrophages, and plasmacytoid dendritic cells. Histologically, DLE skin lesions can initially show inflammation without scarring (DLE-I), and later progress to inflammatory DLE with dermal scarring (DLE-I/S). Characterizing changes in the inflammatory cell infiltrate as DLE lesions develop dermal scarring would elucidate the disease course of DLE. Thus, we sought to characterize the immune cell composition in DLE-I and DLE-I/S skin using immunohistochemistry. 27 untreated lesional skin biopsies showing histologic patterns of inflammation characteristic of DLE were classified into DLE-I and DLE-I/S, based on the presence or absence of dermal scarring. Immunostains for T cells (CD3, CD4, CD8), B cells (CD20), plasmacytoid dendritic cells (CD123), macrophages (CD163), neutrophils (MPO), and plasma cells (CD138) were performed. Two independent observers graded the immunostains on a 0 to 3 scale based on percentage of positive-staining cells (0: <1%, 1: 1-10%, 2: 11-50%, 3: >50%) in three areas, interfollicular interface, perifollicular, and perivascular. We found that CD8+ cells were less frequent in the interfollicular interface (p¼0.01), perifollicular (p<0.0001), and perivascular regions (p¼0.02) in DLE-I/S (N¼18) vs. DLE-I (N¼9) skin. The CD4:CD8 T cell ratio was higher in perifollicular (p<0.0001) and in perivascular (p¼0.003) regions in DLE-I/S skin. DLE-I/S skin had increased CD20+ B cells at the interfollicular interface (p¼0.02) and in perifollicular (p<0.0001) and perivascular regions (p¼0.0003). In summary, the inflammatory infiltrate in DLE skin changes as lesions develop dermal scarring, as evidenced by fewer CD8+ T cells and more CD20+ B cells in DLE-I/S vs. DLE-I skin. These changes could reflect an initial inflammatory process involving cytotoxic T cells that later changes into a heightened B cell response in DLE skin.
Myeloid-derived suppressor cells (MDSC) in psoriasis are an expanded population with diverse T cell-suppressor mechanisms J Chung, L Feigenbaum, P Cruz, B Chong and K Ariizumi Dermatology, The University of Texas Southwestern Medical Center, Dallas, TX Psoriasis is caused by activated T cells that likely are generated from dysregulated immune pathways. In blood and lesional skin of psoriatic patients (as in melanoma), we showed MDSC (the most potent suppressors of T cells) to be highly expanded. Whereas almost all MDSC suppressor function in melanoma is due to MDSC expression of DC-HIL, only w50% of such function in psoriasis is attributable to DC-HIL. We further characterized the function of psoriatic MDSC using the T cell suppression assay: MDSC (CD14+HLA-DR-) and T cells (CD3+) were purified from blood of untreated psoriatic patients and cocultured at different cell ratios in the presence of anti-CD2/3/28 Ab. Psoriatic MDSC inhibited autologous T-cell proliferation and IFN-g/IL-17 responses in a dose-dependent manner and almost completely, but not corresponding allogeneic T-cell responses from healthy individuals (n¼5). In criss/ cross experiments (T cells and MDSC from 2 paired patients switched with each other), we again noted consistent and strong inhibition of autologous responses, disparities for allogeneic responses (inhibited in 4 patients, but not in the other 4). These data suggest that psoriatic T cells may have been differentially primed for susceptibility to the MDSC function. Since the previous data indicate involvement of inhibitory mechanisms other than DC-HIL, we examined effects of various inhibitors on the suppressor function. Anti-IL-10 Ab had no effect, but respective inhibitors for IL-17/arginase and IFN-g/iNOS pathways markedly blocked the T-cell suppression (with a given patient using one or the other pathway but not both, and with no patient showing a mixed pattern). There was no correlations between the ratio of serum IL-17 and IFN-g expression and the tropism to the inhibitory pathway, suggesting that cytokines per se are not critical. Thus psoriatic MDSC are diverse in the use of their inhibitory mechanisms, which may be determined by unidentified attributes of psoriatic T cells.
www.jidonline.org S41
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Skin directed immunotherapies increase tumor infiltrating lymphocytes in patients with cutaneous metastatic breast cancer JY Jung, Y Yuan, S Krishnasamy, T Almazan and J Mortimer City of Hope National Comprehensive Cancer Center, Duarte, CA Cutaneous metastases from breast cancer are common, occurring in 20-30% of patients with metastatic disease and is often the first site of disease recurrence. These metastases are often morbid, leading to significant pain, bleeding and psychological distress. Breast cancer is not considered a classically immunogenic tumor: incidence does not increase in immunosuppressed patients, spontaneous remission is very rare, and clinical trials of systemic immunotherapies such as anti-CTLA4 and anti-PD1 antibodies have shown poor or modest response rates. However, recent evidence suggests that pre-existing tumor infiltrating lymphocytes in breast cancer can predict overall survival and response to therapy. We hypothesized that skin directed therapies could increase the number of tumor infiltrating lymphocytes and ultimately lead to improved clinical response. Of 7 patients treated at our institution, average age was 55 (range 38 to 68 years old) and all had metastatic breast cancer with cutaneous involvement: 3 were ER/PR+, 2 were HER2+, and 2 were triple negative. Three patients received cryotherapy plus topical fluorouracil and 4 patients received a combination of cryotherapy, intra-lesional GM-CSF and imiquimod. Five of seven patients were treated with concurrent endocrine, targeted or chemotherapy. Biopsies available from 4 of the treated patients showed dramatic increases in the number of tumor infiltrating lymphocytes (up to 20 fold). Three patients had complete response in the skin including 2 of the patients (HER2+) demonstrated durable remission. An abscopal, or bystander effect, was noted in un-treated lesions, seen clinically and histologically as early as 2 weeks following treatment. We hypothesize that the skin directed therapies may create an in situ vaccination of the tumor thus enhancing tumor specific immune responses. Skin directed immunotherapies are easily administered, well tolerated and may improve clinical outcomes.
Recipient skin resident memory T cells can induce GvHD-like dermatitis in human engrafted mice TR Matos, KF Lima, A Gehad, CP Elco, EL Lowry, J Teague, S Divito, TS Kupper and R Clark Brigham and Women’s Hospital, Harvard Medical School, Boston, MA Graft-versus-Host-Disease (GvHD) is a major cause of illness and death in patients following hematopoietic stem cell transplantation (SCT). GvHD is assumed to result from donor-derived T cells attacking recipient tissues. However, GvHD is most common in the gut, liver and skin, tissues that contain large populations of long-lived resident memory T cells (TRM). We have found that skin resident T cells survive classic conditioning regimens including total body irradiation and alemtuzumab. We hypothesize that surviving recipient-derived skin resident T cells may contribute to GvHD by interacting with newly generated donor-derived APC that have migrated into skin. To test this hypothesis, we grafted immunodeficient NSG mice with adult human skin containing TRM and then infused them 3 weeks later with equivalent numbers of either allogeneic PBMC (T cells + APC) or monocytes alone (APC). Skin grafts were harvested 3 weeks later and studied by histology, TCR sequencing and RT-PCR. In mice injected with APC alone, the only source of T cells was those resident in the adult skin graft. Mice injected with APC had a GvHD-like dermatitis by histology (mean grade 1.5, vs. 0.25 for saline injected and 2.54 for PBMC injected mice) and had increased numbers of T cells in the skin graft compared to saline injected mice (p<0.01). TCR sequencing confirmed that T cell clones present in the skin before grafting expanded in the skin after exposure to allogeneic APC. Skin grafts from mice infused with APC alone vs. PBMC had similarly elevated levels of IL-17A and TNFa. IL-22 was significantly higher in APC injected mice and IFNg was higher in PBMC injected mice. In summary, interactions between skin resident T cells and infused APC induced T cell proliferation and production of cytokines known to participate in the pathogenesis of GvHD. Our studies support a possible role for TRM in GvHD and suggest that TRM depletion strategies may be helpful in reducing GvHD.
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A mild topical steroid leads to progressive anti-inflammatory effects in skin of moderate-tosevere atopic dermatitis PM Brunner1, S Khattri1,2, S Garcet1, R Finney3, M Oliva1,2, R Dutt1,2, J Fuentes-Duculan1, X Zheng1, X Li1, KM Bonifacio1, N Kunjravia1, I Coats1, I Cueto1, P Gilleaudeau1, M SullivanWhalen1, M Suarez-Farinas2,1, JG Krueger1 and E Guttman-Yassky2,1 1 The Rockefeller University, New York, NY, 2 Icahn School of Medicine at Mount Sinai, New York, NY and 3 Jefferson Medical College, Philadelphia, PA Background: Topical glucocorticosteroids (GCS) are considered an efficient treatment option for atopic dermatitis (AD), but a global assessment of GCS responses on key disease circuits upon weeks-to-months of treatment is currently lacking. Objective: To assess short (4wks) and long-term (16wks) application of topical GCS on AD skin, and define response biomarkers. Methods: Triamcinolone 0.025% cream effects were assessed by gene expression and IHC studies at baseline, 4wks, and 16wks in biopsies from 15 moderate-to-severe AD patients. Results: At 16wks, only 3 patients were clinical responders (using SCORAD50 criteria), but 6 patients qualified as responders based on histological criteria. Baseline characteristics indicated more severe disease in non-responders. While 3/15 patients experienced only transient benefit after 4wks, others showed progressive improvements towards 16wks. Topical GCS use in AD patients resulted in improvements of the AD genomic signature of 25.6% at 4wks and 71.8% at 16wks, respectively, and even 123.9% in the histological responder group. Cytokines (IL-12p40, IL-13, IL-22, CCL17, CCL18, PI3/elafin, S100As) showed consistent decreases from baseline towards 16wks with corresponding improvements in epidermal disease hallmarks (K16, loricrin) in lesional skin from responders (p<0.05). Non-responders largely showed lesser/non-significant reductions of these key inflammatory and barrier markers. The combination of IL-21 and IFN-g baseline expression closely predicted individual clinical GCS responses at 16wks of treatment. Conclusion: Even low-potency GCS can broadly affect immune and barrier responses in moderate-to-severe AD patients, associating higher baseline severity with increased steroid-resistance in AD patients.
Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis S Khattri1,2, PM Brunner1, S Garcet1, R Finney3, SR Cohen4, M Oliva1,2, R Dutt1,2, J FuentesDuculan1, X Zheng1, X Li1, KM Bonifacio1, N Kunjravia1, I Coats1, I Cueto1, P Gilleaudeau1, M Sullivan-Whalen1, M Suarez-Farinas2,1, JG Krueger1 and E Guttman-Yassky2,1 1 The Rockefeller University, New York, NY, 2 Icahn School of Medicine at Mount Sinai, New York, NY, 3 Jefferson Medical College, Philadelphia, PA and 4 Albert Einstein College of Medicine, New York, NY Background: Treatment options for moderate-to-severe atopic dermatitis (AD) are limited. Ustekinumab is an IL-12/IL-23p40 blocker that suppresses Th1, Th17 and Th22 activation, commonly used for psoriasis. Objective: To assess safety and efficacy of ustekinumab in moderate-to-severe AD. Methods: In this phase II, double-blind, placebo-controlled study, 33 patients with moderate-to-severe AD were randomly assigned to either ustekinumab (n¼16) or placebo (n¼17), with subsequent crossover at 16wks, and last dose at 32wks. Background therapy (mild topical steroids) was allowed to increase compliance. Study endpoints included clinical (SCORAD50) and biopsy-based measures of tissue structure and inflammation, using protein and gene expression studies. Results: The ustekinumab group achieved higher SCORAD50 responses at 12, 16 (primary endpoint), and 20wks than placebo, but the difference between groups was not significant. The AD molecular profile/transcriptome showed early robust gene modulation, with sustained further improvements until 40wks, only in the initial ustekinumab-group. Distinct and more robust modulation of Th1, Th17 and Th22 but also Th2-related AD genes was seen only after 4wks of ustekinumab treatment (i.e. MMP12, IL-22, IL-13, IFN-g, elafin/PI3, CXCL1, CCL17; p<0.05). Epidermal responses (K16, terminal differentiation) showed faster (4wks) and long-term regulation (32wks) from baseline in the ustekinumab-group. No severe adverse events were observed. Conclusions:Ustekinumab had clear and sustained clinical and molecular effects, but clinical outcomes might have been obscured by a profound “placebo” effect, most likely due to background topical steroids and possibly too extended treatment intervals.
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Immunohistochemical characterization of inflammatory discoid lupus erythematosus skin with and without dermal scarring JC O’Brien1, GA Hosler2 and B Chong1 1 Dermatology, University of Texas Southwestern Medical Center, Dallas, TX and 2 Propath Dermatopathology, Dallas, TX Discoid lupus erythematosus (DLE) skin predominantly contains CD4+ and CD8+ T cells, B cells, macrophages, and plasmacytoid dendritic cells. Histologically, DLE skin lesions can initially show inflammation without scarring (DLE-I), and later progress to inflammatory DLE with dermal scarring (DLE-I/S). Characterizing changes in the inflammatory cell infiltrate as DLE lesions develop dermal scarring would elucidate the disease course of DLE. Thus, we sought to characterize the immune cell composition in DLE-I and DLE-I/S skin using immunohistochemistry. 27 untreated lesional skin biopsies showing histologic patterns of inflammation characteristic of DLE were classified into DLE-I and DLE-I/S, based on the presence or absence of dermal scarring. Immunostains for T cells (CD3, CD4, CD8), B cells (CD20), plasmacytoid dendritic cells (CD123), macrophages (CD163), neutrophils (MPO), and plasma cells (CD138) were performed. Two independent observers graded the immunostains on a 0 to 3 scale based on percentage of positive-staining cells (0: <1%, 1: 1-10%, 2: 11-50%, 3: >50%) in three areas, interfollicular interface, perifollicular, and perivascular. We found that CD8+ cells were less frequent in the interfollicular interface (p¼0.01), perifollicular (p<0.0001), and perivascular regions (p¼0.02) in DLE-I/S (N¼18) vs. DLE-I (N¼9) skin. The CD4:CD8 T cell ratio was higher in perifollicular (p<0.0001) and in perivascular (p¼0.003) regions in DLE-I/S skin. DLE-I/S skin had increased CD20+ B cells at the interfollicular interface (p¼0.02) and in perifollicular (p<0.0001) and perivascular regions (p¼0.0003). In summary, the inflammatory infiltrate in DLE skin changes as lesions develop dermal scarring, as evidenced by fewer CD8+ T cells and more CD20+ B cells in DLE-I/S vs. DLE-I skin. These changes could reflect an initial inflammatory process involving cytotoxic T cells that later changes into a heightened B cell response in DLE skin.
Myeloid-derived suppressor cells (MDSC) in psoriasis are an expanded population with diverse T cell-suppressor mechanisms J Chung, L Feigenbaum, P Cruz, B Chong and K Ariizumi Dermatology, The University of Texas Southwestern Medical Center, Dallas, TX Psoriasis is caused by activated T cells that likely are generated from dysregulated immune pathways. In blood and lesional skin of psoriatic patients (as in melanoma), we showed MDSC (the most potent suppressors of T cells) to be highly expanded. Whereas almost all MDSC suppressor function in melanoma is due to MDSC expression of DC-HIL, only w50% of such function in psoriasis is attributable to DC-HIL. We further characterized the function of psoriatic MDSC using the T cell suppression assay: MDSC (CD14+HLA-DR-) and T cells (CD3+) were purified from blood of untreated psoriatic patients and cocultured at different cell ratios in the presence of anti-CD2/3/28 Ab. Psoriatic MDSC inhibited autologous T-cell proliferation and IFN-g/IL-17 responses in a dose-dependent manner and almost completely, but not corresponding allogeneic T-cell responses from healthy individuals (n¼5). In criss/ cross experiments (T cells and MDSC from 2 paired patients switched with each other), we again noted consistent and strong inhibition of autologous responses, disparities for allogeneic responses (inhibited in 4 patients, but not in the other 4). These data suggest that psoriatic T cells may have been differentially primed for susceptibility to the MDSC function. Since the previous data indicate involvement of inhibitory mechanisms other than DC-HIL, we examined effects of various inhibitors on the suppressor function. Anti-IL-10 Ab had no effect, but respective inhibitors for IL-17/arginase and IFN-g/iNOS pathways markedly blocked the T-cell suppression (with a given patient using one or the other pathway but not both, and with no patient showing a mixed pattern). There was no correlations between the ratio of serum IL-17 and IFN-g expression and the tropism to the inhibitory pathway, suggesting that cytokines per se are not critical. Thus psoriatic MDSC are diverse in the use of their inhibitory mechanisms, which may be determined by unidentified attributes of psoriatic T cells.
www.jidonline.org S41