Modulation of T Cell Function by Alpha-Fetoprotein: An in vivo Study on Porcine Thyroid Peroxidase-Induced Experimental Autoimmune Thyroiditis in Transgenic Mice Producing Human Alpha-Fetoprotein

Matsuura, Eiji; Kang, Yejin; H, Kitakawa; Ogata, Akihiko; Kotani, Takuya; Ohtaki, Sachiya; Nishi, Shinzo

doi:10.1159/000030059

Cited by 23 publications

(10 citation statements)

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“…24 In addition, the effect of AFP on immune cells is controversial with reports finding both stimulatory and inhibitory effects. [25][26][27][28][29][30][31][32][33][34][35][36] We have demonstrated that human and murine CD8 + T cells can recognize peptide epitopes derived from AFP. [37][38][39][40][41][42][43][44] We have also tested major histocompatibility complex (MHC) class I peptide-based vaccines in AFP+HCC subjects.…”

Section: Abstract Dendritic Cells; T Cells; Antigen Presentation; Vacmentioning

confidence: 99%

AFP-specific CD4+ Helper T-cell Responses in Healthy Donors and HCC Patients

Evdokimova¹,

Liu²,

Potter³

et al. 2007

Journal of Immunotherapy

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SummaryHepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and is often diagnosed at an advanced stage. We have investigated α-fetoprotein (AFP) as a tumor-associated antigen for HCC. We identified major histocompatibility complex class I-restricted peptide epitopes derived from AFP and studied CD8 + T-cell responses in vivo and in vitro in ongoing immunotherapy studies. Helper T cells are of critical importance in shaping the immune response; therefore, we investigated the frequency and function of AFP-specific CD4 + T cells in the general population and among HCC patients. CD4 + T-cell responses were assessed by direct ex vivo multicytokine enzyme-linked immunospot assay and by measurement of cytokine levels using a multicytokine assay. Our analysis indicates that healthy donors have very low frequencies of AFPspecific CD4 + T-cell responses, which are of T H 1 type, detectable ex vivo. In contrast, these T cells were either reduced or eliminated in HCC patients at advanced stages of disease. To better activate these cells, we compared the stimulatory capacity of both AFP protein-fed and AdVhAFP-engineered dendritic cells (DC). Healthy donors have CD4 + T-cell responses, which were activated in response to AFP protein-fed DC whereas HCC patients do not demonstrate significant responses to AFP protein. AdVhAFP-transduced DC were capable of activating higher frequency T H 1 CD4 + responses to AFP in both healthy donors and AFP-positive HCC patients. Importantly, CD4 + T-cell cytokine expression profiles were skewed towards interleukin-2 and interferon-γ production when activated by adenovirally engineered DC, which has therapeutic implications for vaccination efforts. Financial Disclosure: One of the authors is a coinventor on a recently granted US Patent (L. H. B., US Patent No. 7,098,306, "Method and compositions for treating hepatocellular cancer," granted August 2006), which covers some of the MHC class I peptides used in a recently published clinical trial testing AFP class I peptides pulsed onto autologous DC. The intellectual property is owned by the University of California, has not been licensed, and there has been no financial interest for the inventors, to date. The HCC patient PBMC samples used in this work were from that clinical trial. The remaining authors have declared there are no financial conflicts of interest related to this work. [1][2][3] However, the majority of cases are detected at advanced stages, which, even if adequately treated locally, relapse systemically, and HCC recurs in 75% to 100% of patients at 5 years. 4 There are no effective systemic therapies for this disease. 5,6 This leads to a 9% 5-year survival rate after diagnosis in the United States, the second lowest survival rate for any type of cancer. 7 NIH Public Accessα-fetoprotein (AFP) is the most common serum protein during embryonic development, and is a physiologic counterpart of adult serum albumin. Suppression of AFP synthesis occurs shortly after birth. However, AFP mRNA can be detected in hum...

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Section: Abstract Dendritic Cells; T Cells; Antigen Presentation; Vacmentioning

confidence: 99%

AFP-specific CD4+ Helper T-cell Responses in Healthy Donors and HCC Patients

Evdokimova¹,

Liu²,

Potter³

et al. 2007

Journal of Immunotherapy

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show abstract

“…AFP treatment improved the clinical severity of experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune MG (EAMG) [6,[12][13][14][15]. Moreover, transgenic mice overexpressing human AFP (hAFP) were less susceptible to experimental autoimmune thyroiditis and experimental antigen-induced arthritis [16,17]. Based on the pre-clinical data, a randomized, double-blind, placebo-controlled trial of the recombinant hAFP (rhAFP) was performed in patients with active RA [18].…”

Section: Introductionmentioning

confidence: 99%

Immunomodulation of EAE by alpha-fetoprotein involves elevation of immune cell apoptosis markers and the transcription factor FoxP3

Irony-Tur-Sinai

Grigoriadis

Tsiantoulas

et al. 2009

Journal of the Neurological Sciences

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“…a-Fetoprotein (AFP) is a major serum protein secreted primarily by the embryonic liver and yolk sac during perinatal develop-ment. 7,8 By the end of the second month postpartum, only trace amounts of AFP can be detected in the circulation, and it is almost completely replaced by human serum albumin 9,10 AFP is one of the most important markers in the diagnosis of primary HCC and yolk sac tumors, 11,12 and inappropriate expression of the developmentally silenced AFP gene in the adult liver occurs in 70% to 85% of all HCC cases. 13,14 Several authors have reported AFP as an independent predictor of poor prognosis, even in patients receiving curative hepatectomy.…”

Section: Introductionmentioning

confidence: 99%