화상환자에서 면역억제 기전

정태호,황일우,장수일,김문규,서정민,정치영,김정철 慶北大學校 醫科大學 1995 慶北醫大誌 Vol.36 No.4

목적 : 본 연구는 화상환자에서 면역이상의 기전을 조사코져 T-세포의 활성을 나타내는 가용성 interleukin-2 수용체(IL-2R), 대식세포의 활성을 나타내는 neopterin, tumor necrosis factor(TNF) 및 interleukin-6 (IL-6), 그리고 호중구의 활성을 반영하는 elastase-α1-antitrypsin을 측정하였다. 또한 lipopolysaccharide(LPS)가 이들 면역세포의 활성화에 미치는 영향을 조사하였다. 대상 및 방법 : 30예의 화상환자를 대상으로 화상후 1일, 7일, 14일, 21일, 28일에 각각 혈액을 채취하여 혈청중 가용성 IL-2R, TNF, IL-6, 그리고 elastase-α1-antitrypsin은 각각 효소면역법으로, 혈청중 neopterin은 radioimmunoassay법으로 측정하였다. LPS가 말초 단핵세포에 미치는 영향은 역전사 중합효소 연쇄반응을 통하여 각종 cytokines의 mRNA 발현을 측정하였다. 결과 : 화상환자에서 혈청중 가용성 IL-2R은 화상후 1일째부터 대조군에 비하여 유의성 있게 증가되어 7일과 14일째에 최고치를 나타냈으며 그 이후에는 다소 감소하였으나 대조군보다는 유의한 증가를 나타냈다. 화상환자를 중화상, 중등도화상, 경도화상으로 분류하여 혈청중 가용성 IL-2R 치를 비교해본 결과 중증 화상일수록 더욱 높은 치를 나타냈다. 화상환자에서 혈청중 neopterin 역시 화상후 1일째부터 증가되어 전 관찰기간 동안 대조군에 비해 유의한 높은 치를 나타냈다. 경도화상과 중등도 화상에서는 서로 유의한 차이를 보이지 않았으나 중환자에서는 경도 혹은 중등도 화상환자에 비해 유의한 증가를 보였다. 화상환자에서 혈청중 TNF 농도는 화상후 1일부터 증가되어 관찰전기간에 걸쳐 유의한 증가를 나타냈으며 중등도 화상환자에서 가장 높은 치를 보였다. 혈청중 IL-6치 역시 화상 전기간에 걸쳐 대조군보다 유의한 증가를 나타냈으며 중화상 환자에서 가장 높은 치를 나타냈다. 화상은 또한 혈청중 elastase-α1-antitrypsin 농도를 현저히 증가시켰다. 즉 화상후 1일에 elastase-α1-antitrypsin 농도는 정상인보다 5배 높았으며 그 이후 약 4주간 계속 높은 농도를 유지하다가 환자가 회복되면서 감소하는 경향을 나타내었다. 중등도화상 및 중화상환자의 혈청중 elastase-α1-antitrypsin 농도는 경도 화상환자에서 비해 유의한 증가를 보였다. 한편 화상환자에서 면역이상을 초래하는 주된 요인으로 여겨지는 lipopolysaccharide는 면역세포를 총체적으로 활성화시켜 IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF, IFN-γ, TGF-β, GM-CSF, IL-2R의 유전자발현을 현저히 증가시켰다. 결론 : 화상환자에서 T-세포, 대식세포, 호중구의 활성화를 반영하는 가용성 IL-2R, neopterin, ,TNF, IL-6, elastase-α1-antitrypsin치가 혈중에 증가되어 있으며 화상의 정도가 심할수록 더 높았다. Cell-mediated immunity frequently becomes severely impaired after thermal injury. However, the cause of postburn immune dysfunction is unclear and controversy exists over both pathophysiology and clinical relevance of these abnormalities. This study was undertaken to investigate the immune responses in vivo of patients with burn. Levels of soluble IL-2R, a sensitive marker of T-cell activation, levels of serum TNF, IL-6, and neopterin, an index of macrophage activation, and levels of serum elastase-α1-antitrypsin, an index of neutrophil activation, were measured in serial serum samples taken from 30 burned patients. In patients with burn, soluble IL-2R levels were increased over a 4-week interval with peak concentrations reached during the 2nd week after burn. Patients with severe burn showed a higher soluble IL-2R levels than those with mild or moderate burn. In addition soluble IL-2R significantly correlated with burn size. The levels of serum neopterin were already increased at the first day following burn, and remained at a high level throughout the total period studied (28 days). Patients with severe burn showed significantly higher concentration of serum neopterin than mild or moderate burn. There was positive relationship between the burn sizes and the levels of neopterin. A significant positive correlation was also found between serum soluble IL-2R levels and neopterin levels in burn patients. Levels of serum TNF and IL-6 were also significantly increased over a 4-week interval in burn patients. The levels of serum elastase-α1-antitrypsin were also already increased at the first day following burn, and remained at a high level over a 4-week. Patients with moderate or severe burn showed significantly higher concentration of serum elastase-α1-antitrypsin than those with mild burn. There was no significant relationship between the burn extent and the level of elastase-α1-antitrypsin. LPS increased the transcription of all the cytokines we examined in peripheral mononuclear cells, i.e., IL-1α, IL-1β, IL-2, IL-4, IL-5_IL-6, IL-8, IL-10, TNF, TGF-β, GM-CSF, and IL-2R. We conclude that soluble IL-2R, neopterin, TNF, IL-6, and elastase-α1-antitrypsin might be useful parameters for monitoring of the clinical course in burn patients. Moreover, they indicate that T-cell, macrophage, and neutrophil activation might play the central role in the pathogenesis of the immuno-logic and metabolic disturbance that follows thermal injury.

Gene therapy of intracranial glioma using interleukin 12-secreting human umbilical cord blood-derived mesenchymal stem cells.

Ryu, Chung Heon,Park, Sang-Hoon,Park, Soon A,Kim, Seong Muk,Lim, Jung Yeon,Jeong, Chang Hyun,Yoon, Wan-Soo,Oh, Won-il,Sung, Young Chul,Jeun, Sin-Soo Mary Ann Liebert 2011 Human gene therapy Vol.22 No.6

<P>Clinical trials of gene therapy using a viral delivery system for glioma have been limited. Recently, gene therapy using stem cells as the vehicles for delivery of therapeutic agents has emerged as a new treatment strategy for malignant brain tumors. In this study, we used human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) as delivery vehicles with glioma-targeting capabilities, and modified interleukin-12 (IL-12p40N220Q; IL-12M) as a novel therapeutic gene. We also engineered UCB-MSCs to secret IL-12M (UCB-MSC-IL12M) via tetrameric cell-permeable peptide (4HP4)-mediated adenoviral transduction. We confirmed the migratory capacity of UCB-MSC-IL12M toward GL26 mouse glioma cells by an in vitro migration assay and in vivo injection of UCB-MSC-IL12M into the ipsilateral hemisphere of implanted gliomas in C57BL/6 mice. In vivo efficacy experiments showed that intratumoral injection of UCB-MSC-IL12M significantly inhibited tumor growth and prolonged the survival of glioma-bearing mice compared with control mice. Antitumor effects were associated with increased local IL-12M levels, followed by interferon-γ secretion and T-cell infiltration in intracranial gliomas, as well as antiangiogenesis. Interestingly, tumor-free mice after UCB-MSC-IL12M treatment were resistant to ipsilateral and contralateral tumor rechallenge, which was closely associated with tumor-specific long-term T-cell immunity. Thus, our results provide the rationale for designing novel experimental protocols to induce long-term antitumor immunity against intracranial gliomas using UCB-MSCs as an effective delivery vehicle for therapeutic cytokines including IL-12M.</P>

The Correlation of Serum IL-12B Expression With Disease Activity in Patients With Inflammatory Bowel Disease

Lee, Hye Won,Chung, Sook Hee,Moon, Chang Mo,Che, Xiumei,Kim, Seung Won,Park, Soo Jung,Hong, Sung Pil,Kim, Tae Il,Kim, Won Ho,Cheon, Jae Hee Williams & Wilkins Co 2016 Medicine Vol.95 No.23

<▼1><P>Supplemental Digital Content is available in the text</P></▼1><▼2><P><B>Abstract</B></P><P>Genetic variants in <I>IL12B</I>, encoding the p40 subunit common in interleukin-12 (IL-12) and interleukin-23, were identified as the susceptibility loci for inflammatory bowel disease (IBD). This study aimed to identify the correlation of serum IL-12B expression with disease activity in patients with IBD and evaluate the possibility of IL-12B as a biomarker for assessing inflammatory status in IBD.</P><P>A total of 102 patients with IBD, including 38, 32, and 32 patients with Crohn's disease (CD), ulcerative colitis (UC), and intestinal Behçet's disease (intestinal BD), respectively, were included. The clinical and laboratory data from the patients were collected at the time of serum IL-12B measurement. Serum IL-12B levels were measured using an enzyme-linked immunosorbent assay.</P><P>The median IL-12B levels in patients with CD, UC, and intestinal BD were significantly higher than those in controls (1.87, 2.74, and 2.73 pg/mL, respectively, vs. 1.42 pg/mL, all <I>P</I> <0.05). IL-12B concentrations were associated with disease activity in patients with UC and intestinal BD but not in those with CD. IL-12B levels were increased with increasing disease activity in patients with UC (<I>P</I> <0.001). Likewise, patients with active intestinal BD had higher IL-12B levels than those without active disease (<I>P</I> = 0.008). IL-12B levels were correlated with the endoscopic disease activity of UC (<I>P</I> = 0.002) and intestinal BD (<I>P</I> = 0.001) but not that of CD.</P><P>Serum IL-12B levels were significantly correlated with clinical and endoscopic disease activity in patients with UC and intestinal BD, suggesting its potential use as a biomarker for assessing disease activity in these patients.</P></▼2>

Genetic effect of <i>CCR3</i> and <i>IL5RA</i> gene polymorphisms on eosinophilia in asthmatic patients

Lee, June-Hyuk,Chang, Hun Soo,Kim, Ji Hyun,Park, Se-Min,Lee, Yong Mok,Uh, Soo Taek,Rhim, Taiyoun,Chung, Il Yup,Kim, Yong-Hoon,Park, Byung Lae,Park, Choon-Sik,Shin, Hyoung Doo Elsevier 2007 The journal of allergy and clinical immunology Vol.120 No.5

<P><B>Background</B></P><P>Eosinophilic infiltration and peripheral blood eosinophilia in asthma require the cooperation of eosinophil-specific cytokines and chemokines and their receptors.</P><P><B>Objective</B></P><P>We investigated the association of polymorphisms in <I>CCR3</I> and <I>IL5RA</I> with asthma susceptibility or peripheral blood eosinophilia and the effects of the polymorphisms on receptor expression.</P><P><B>Methods</B></P><P>Polymorphisms in <I>CCR3</I> and <I>IL5RA</I> were identified and genotyped in 576 asthmatic patients and 180 healthy control subjects. CCR3 and IL-5 receptor α (IL-5Rα) protein expression on eosinophils was measured by means of flow cytometry.</P><P><B>Results</B></P><P>Although polymorphisms in <I>CCR3</I> were not associated with asthma susceptibility, the <I>CCR3</I> haplotype <I>ht2</I> showed a negative gene dose effect on the eosinophil count (<I>P</I> = .003–.009). <I>IL5RA c.−5091G>A</I> was weakly associated with eosinophil count. The effects of <I>ht2</I> were greater when paired with <I>IL5RA c.−5091A</I> (<I>P</I> = .001–.002). CCR3 protein expression was higher on eosinophils of asthmatic patients without <I>ht2</I> than in those with <I>ht2</I>. Asthmatic patients with the <I>IL5RA c.−5091A</I> allele showed higher IL-5Rα expression than those who were homozygous for the G allele.</P><P><B>Conclusion</B></P><P>The genetic association between <I>CCR3</I> polymorphisms and the number of circulating eosinophils was revealed as a novel finding. These associations were more pronounced when the <I>CCR3</I> polymorphisms were paired with polymorphisms in <I>IL5RA</I>. The protein expression levels of CCR3 and IL-5Rα on peripheral blood eosinophils are associated with the polymorphisms on their own genes.</P><P><B>Clinical implications</B></P><P>The identification of single nucleotide polymorphisms and haplotypes of <I>CCR3</I> and <I>IL5RA</I> might be useful in developing markers for intermediate phenotypes of eosinophil number and in designing strategies to control diseases related to hypereosinophilia.</P>

A novel role for bone-derived cells in ankylosing spondylitis: Focus on IL-23

Jo, Sungsin,Koo, Bon San,Lee, Bitnara,Kwon, Eunji,Lee, Young Lim,Chung, Heekyoung,Sung, Il-Hoon,Park, Ye-Soo,Kim, Tae-Hwan Elsevier 2017 Biochemical and biophysical research communication Vol. No.

<P><B>Abstract</B></P> <P>The main aim of this study are to explore the role of bone-derived cells (BdCs) in ankylosing spondylitis (AS) and determine the underlying molecular mechanisms of IL-23 production. Primary BdCs were isolated from diced bone of facet joints obtained during surgery from seven AS patients and seven disease control (Ct) patients. Osteoblastic activity of BdCs was assessed by measuring their alkaline phosphatase activity and by alizarin red staining. Osteoblast and endoplasmic reticulum (ER) stress-related genes were assessed by quantitative PCR, immunoblotting, immunofluorescence, and immunohistochemistry. In addition, expression of IL-23 in response to BIX (selective BIP inducer X)-induced ER stress was evaluated by qPCR and ELISA. Protein interaction and binding to IL-23 promoter were confirmed by Immunoprecipitation and Chromatin immunoprecipitation, respectively. Transcript levels of genes involved in osteoblast function, as well as of the ER stress marker were higher in the AS group than the Ct group, and elevated RUNX2, BiP and IL-23 expression were observed in the BdCs, serum, and bone biopsies from the AS group. BIX-induced ER stress stimulated osteoblastic activity and IL-23 secretion by upregulating RUNX2 expression. Furthermore, in AS BdCs, RUNX2 interacted with C/EBPβ to bind to IL-23 promoter and RUNX2 knockdown suppressed IL-23 secretion. These finding may provide a molecular mechanism involved in sustained ER stress in AS BdCs stimulates the activation of RUNX2 and C/EBPβ genes, leading to IL-23 production.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Bones and its-derived cells from patients with AS showed an increase in ER stress. </LI> <LI> IL-23 cytokine was significantly higher in AS patients than in healthy controls. </LI> <LI> Inducing ER stress in AS exhibited an increase of bone-related genes. </LI> <LI> Inducing ER stress in AS was accompanied with augmentation of IL-23 cytokine. </LI> <LI> ER stress-induced RUNX2 is involved in IL-23 secretion and bone-related genes. </LI> </UL> </P>

Glucocorticoid-induced tumor necrosis factor receptor–related protein co-stimulation facilitates tumor regression by inducing IL-9–producing helper T cells

Kim, Il-Kyu,Kim, Byung-Seok,Koh, Choong-Hyun,Seok, Jae-Won,Park, Jun-Seok,Shin, Kwang-Soo,Bae, Eun-Ah,Lee, Ga-Eun,Jeon, Hyewon,Cho, Jaebeom,Jung, Yujin,Han, Daehee,Kwon, Byoung S,Lee, Ho-Young,Chung, Nature Publishing Group, a division of Macmillan P 2015 Nature medicine Vol.21 No.9

<P>T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) elicits antitumor activity in various tumor models; however, the underlying mechanism of action remains unclear. Here we demonstrate a crucial role for interleukin (IL)-9 in antitumor immunity generated by the GITR agonistic antibody DTA-1. IL-4 receptor knockout (Il4ra(-/-)) mice, which have reduced expression of IL-9, were resistant to tumor growth inhibition by DTA-1. Notably, neutralization of IL-9 considerably impaired tumor rejection induced by DTA-1. In particular, DTA-1-induced IL-9 promoted tumor-specific cytotoxic T lymphocyte (CTL) responses by enhancing the function of dendritic cells in vivo. Furthermore, GITR signaling enhanced the differentiation of IL-9-producing CD4(+) T-helper (T(H)9) cells in a TNFR-associated factor 6 (TRAF6)- and NF-kappa B-dependent manner and inhibited the generation of induced regulatory T cells in vitro. Our findings demonstrate that GITR co-stimulation mediates antitumor immunity by promoting T(H)9 cell differentiation and enhancing CTL responses and thus provide a mechanism of action for GITR agonist-mediated cancer immunotherapies.</P>

주조직적합항원이 불일치하는 마우스 동종 조혈모세포이식에서 IL-2로 유도된 CD4+CD25+ T세포를 이용한 이식편대숙주병의 억제

현재호,정대철,정낙균,박수정,민우성,김태규,최병옥,김원일,한치화,김학기,Hyun, Jae Ho,Jeong, Dae Chul,Chung, Nak Gyun,Park, Soo Jeong,Min, Woo Sung,Kim, Tai Gyu,Choi, Byung Ock,Kim, Won Il,Han, Chi Wha,Kim, Hack Ki 대한면역학회 2003 Immune Network Vol.3 No.4

Background: In kidney transplantation, donor specific transfusion may induce tolerance as a result of some immune regulatory cells against the graft. In organ transplantation, the immune state arises from a relationship between the immunocompromised graft and the immunocompetent host. However, a reverse immunological situation exists between the graft and the host in hematopoietic stem cell transplantation (HSCT). In addition, early IL-2 injections after an allogeneic murine HSCT have been shown to prevent lethal graft versus host disease (GVHD) due to CD4+ cells. We investigated the induction of the regulatory CD4+CD25+ cells after a transfusion of irradiated recipient cells with IL-2 into a donor. Methods: The splenocytes (SP) were obtained from 6 week-old BALB/c mice ($H-2^d$) and irradiated as a single cell suspension. The donor mice (C3H/He, $H-2^k$) received $5{\times}10^6$ irradiated SP, and 5,000 IU IL-2 injected intraperitoneally on the day prior to HSCT. The CD4+CD25+ cell populations in SP treated C3H/He were analyzed. In order to determine the in vivo effect of CD4+CD25+ cells, the lethally irradiated BALB/c were transplanted with $1{\times}10^7$ donor BM and $5{\times}10^6$ CD4+CD25+ cells. The other recipient mice received either $1{\times}10^7$ donor BM with $5{\times}10^6$ CD4+ CD25- cells or the untreated SP. The survival and GVHD was assessed daily by a clinical scoring system. Results: In the MLR assay, BALB/c SP was used as a stimulator with C3H/He SP, as a responder, with or without treatment. The inhibition of proliferation was $30.0{\pm}13%$ compared to the control. In addition, the MLR with either the CD4+CD25+ or CD4+CD25- cells, which were isolated by MidiMacs, from the C3H/He SP treated with the recipient SP and IL-2 was evaluated. The donor SP treated with the recipient cells and IL-2 contained more CD4+CD25+ cells ($5.4{\pm}1.5%$) than the untreated mice SP ($1.4{\pm}0.3%$)(P<0.01). There was a profound inhibition in the CD4+CD25+ cells ($61.1{\pm}6.1%$), but a marked proliferation in the CD4+CD25- cells ($129.8{\pm}65.2%$). Mice in the CD4+CD25+ group showed low GVHD scores and a slow progression from the post-HSCT day 4 to day 9, but those in the control and CD4+CD25- groups had a high score and rapid progression (P<0.001). The probability of survival was 83.3% in the CD4+CD25+ group until post-HSC day 35 and all mice in the control and CD4+CD25- groups died on post-HSCT day 8 or 9 (P=0.0105). Conclusion: Donor graft engineering with irradiated recipient SP and IL-2 (recipient specific transfusion) can induce abundant regulatory CD4+CD25+ cells to prevent GVHD.

Interferon-γ Inhibits in vitro Mobilization of Eosinophils by Interleukin-5

Park, Choon-Sik,Choi, Eun Nam,Kim, Jung Sun,Choi, Yun Sung,Rhim, Tai Youn,Chang, Hun Soo,Chung, Il Yup S. Karger AG 2005 International archives of allergy and immunology Vol.136 No.3

<P><I>Background:</I> Th2 cytokines play pivotal roles in allergic inflammation, including eosinophilia, and their actions are antagonized by Th1 cytokines, conferring them therapeutic potential. <I>Methods:</I> In this study, we examined the ability of a number of cytokines to suppress the activation of eosinophils that function as effector cells for allergic airway diseases. <I>Results:</I> Interleukin (IL)-5, IL-6, and tumor necrosis factor (TNF) induced an eosinophil shape change, whereas interferon (IFN)-γ significantly inhibited the shape change. Other cytokines, including IL-1β, IL-4, IL-10 and IL-13, had little or only slightly enhancing or reducing effects on the shape change. We further analyzed the IFN-γ effect, showing that pretreatment with IFN-γ strongly suppressed IL-5-induced eosinophil shape change, and cycloheximide (CHX) abrogated the suppression by IFN-γ, suggesting that new protein synthesis is required for the inhibitory effect by this cytokine. In agreement with these results, IFN-γ blocked the eosinophil migration and ERK phophorylation induced by IL-5, and the addition of CHX restored eosinophil chemotaxis. <I>Conclusions:</I> Collectively, IFN-γ may attenuate eosinophilic inflammation by directly negating eosinophil mobilization.</P><P>Copyright © 2005 S. Karger AG, Basel</P>

Protective Effects of Acorn (Quercus acutissima CARR.) against IgE-mediated Allergic and Ovalbumin (OVA)-Induced Asthmatic Responses via Inhibition of Oxidative Stress

Chung, Mi-Ja,Jo, Hang-Soo,Choi, Ha-Na,Cho, Soo-Muk,Park, Yong-Il The Korean Society of Pharmaceutical Sciences and 2011 Journal of Pharmaceutical Investigation Vol.41 No.6

This work was performed to investigate the protective effect of ethanol extract (AEx) from acorn (Quercus acutissima CARR.) against allergic mediated responses in asthma model cells and mice. The AEx inhibited antigen-stimulated cytokine production such as interleukin (IL)-4, IL-13 and tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and AEx also inhibited intracellular reactive oxygen species (ROS) generation against IgE-mediated allergic response in rat basophilic leukaemia RBL-2H3 cells. The ovalbumin (OVA)-sensitized mice were orally administered with AEx (100 or 300 mg/kg) and authentic tannic acid (75 mg/kg) every day for 15 days. Increased TNF-${\alpha}$ production by OVA-sensitization/challenge was significantly reduced by administration of AEx. The serum triglyceride levels of asthma mice were significantly reduced after feeding for 15 days with tannic acid or AEx. The mice fed with tannic acid or AEx also exhibited a significant reduction in body weights compared to those of asthma control group. The AEx increased the heme oxygenase (HO)-1 mRNA expression in the asthma model mice and showed DPPH radical scavenging activity. These results indicate that AEx protects against IgEmediated allergic and OVA-induced asthmatic responses via direct and indirect antioxidant activities. Reduced triglyceride and body weights may provide additional protective benefits of AEx on allergic asthma.

GM-CSF Promotes Antitumor Immunity by Inducing Th9 Cell Responses

Kim, Il-Kyu,Koh, Choong-Hyun,Jeon, Insu,Shin, Kwang-Soo,Kang, Tae-Seung,Bae, Eun-Ah,Seo, Hyungseok,Ko, Hyun-Ja,Kim, Byung-Seok,Chung, Yeonseok,Kang, Chang-Yuil American Association for Cancer Research 2019 Cancer immunology research Vol.7 No.3

<P>Granulocyte-macrophage colony-stimulating factor (GM-CSF) functions as an adjuvant for antitumor immunity through an unclear mechanism. By activating monocyte-derived dendritic cells, GM-CSF induces Th9 development and IL9 production, which facilitates antitumor cytotoxic T lymphocyte responses.</P><P>GM-CSF as an adjuvant has been shown to promote antitumor immunity in mice and humans; however, the underlying mechanism of GM-CSF–induced antitumor immunity remains incompletely understood. In this study, we demonstrate that GM-CSF potentiates the efficacy of cancer vaccines through IL9-producing Th (Th9) cells. GM-CSF selectively enhanced Th9 cell differentiation by regulating the COX2–PGE<SUB>2</SUB> pathway while inhibiting the differentiation of induced regulatory T (iTreg) cells <I>in vitro</I> and <I>in vivo</I>. GM-CSF–activated monocyte-derived dendritic cells converted tumor-specific nai¨ve Th cells into Th9 cells, and delayed tumor growth by inducing antitumor CTLs in an IL9-dependent manner. Our findings reveal a mechanism for the adjuvanticity of GM-CSF and provide a rationale for the use of GM-CSF in cancer vaccines.</P>