574 The in-vivo effect of colchicine on clinical parameters and supressor T-cell function in patients with allergic bronchial asthma

T cells are key immune cells involved in the pathogenesis of several diseases, rendering them important therapeutic targets. Although drug delivery to T cells is the subject of continuous research, it remains challenging to deliver drugs to primary T cells. Here, we used a peptide-based drug delivery system, AP, which was previously developed as a transdermal delivery peptide, to modulate T cell function. We first identified that AP-conjugated enhanced green fluorescent protein (EGFP) was efficiently delivered to non-phagocytic human T cells. We also confirmed that a nine-amino acid sequence with one cysteine residue was the optimal sequence for protein delivery to T cells. Next, we identified the biodistribution of AP-dTomato protein in vivo after systemic administration, and transduced it to various tissues, such as the spleen, liver, intestines, and even to the brain across the blood–brain barrier. Next, to confirm AP-based T cell regulation, we synthesized the AP-conjugated cytoplasmic domain of CTLA-4, AP-ctCTLA-4 peptide. AP-ctCTLA-4 reduced IL-17A expression under Th17 differentiation conditions in vitro and ameliorated experimental autoimmune encephalomyelitis, with decreased numbers of pathogenic IL-17A+GM-CSF+ CD4 T cells. These results collectively suggest the AP peptide can be used for the successful intracellular regulation of T cell function, especially in the CNS.

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Combined Deficiency of p50 and cRel in CD4+ T Cells Reveals an Essential Requirement for Nuclear Factor κB in Regulating Mature T Cell Survival and In Vivo Function

Journal of Experimental Medicine ◽

10.1084/jem.20021610 ◽

2003 ◽

Vol 197 (7) ◽

pp. 861-874 ◽

Cited By ~ 94

Author(s):

Ye Zheng ◽

Monika Vig ◽

Jesse Lyons ◽

Luk Van Parijs ◽

Amer A. Beg

Keyword(s):

T Cells ◽

T Cell ◽

Cell Survival ◽

Cd4 T Cells ◽

Cell Function ◽

Nuclear Factor ◽

T Cell Function ◽

T Cell Survival

Signaling pathways involved in regulating T cell proliferation and survival are not well understood. Here we have investigated a possible role of the nuclear factor (NF)-κB pathway in regulating mature T cell function by using CD4+ T cells from p50−/− cRel−/− mice, which exhibit virtually no inducible κB site binding activity. Studies with these mice indicate an essential role of T cell receptor (TCR)-induced NF-κB in regulating interleukin (IL)-2 expression, cell cycle entry, and survival of T cells. Our results further indicate that NF-κB regulates TCR-induced expression of antiapoptotic Bcl-2 family members. Strikingly, retroviral transduction of CD4+ T cells with the NF-κB–inducing IκB kinase β showed that NF-κB activation is not only necessary but also sufficient for T cell survival. In contrast, our results indicate a lack of involvement of NF-κB in both IL-2 and Akt-induced survival pathways. In vivo, p50−/− cRel−/− mice showed impaired superantigen-induced T cell responses as well as decreased numbers of effector/memory and regulatory CD4+ T cells. These findings provide the first demonstration of a role for NF-κB proteins in regulating T cell function in vivo and establish a critically important function of NF-κB in TCR-induced regulation of survival.

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Evaluation of CD4+T Cell Function In Vivo in HIV‐Infected Patients as Measured by Bacteriophage phiX174 Immunization

The Journal of Infectious Diseases ◽

10.1086/315739 ◽

2000 ◽

Vol 182 (2) ◽

pp. 435-441 ◽

Cited By ~ 51

Author(s):

Ilana Fogelman ◽

Victoria Davey ◽

Hans D. Ochs ◽

Michael Elashoff ◽

Mark B. Feinberg ◽

...

Keyword(s):

T Cell ◽

Cell Function ◽

Cd4 T Cell ◽

T Cell Function ◽

Bacteriophage Phix174

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CD3 limits the efficacy of TCR gene therapy in vivo

Blood ◽

10.1182/blood-2011-04-346338 ◽

2011 ◽

Vol 118 (13) ◽

pp. 3528-3537 ◽

Cited By ~ 64

Author(s):

Maryam Ahmadi ◽

Judith W. King ◽

Shao-An Xue ◽

Cécile Voisine ◽

Angelika Holler ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Function ◽

Cell Receptor ◽

Surface Expression ◽

T Cell Function ◽

Engineered T Cells ◽

Rate Limiting

Abstract The function of T-cell receptor (TCR) gene modified T cells is dependent on efficient surface expression of the introduced TCR α/β heterodimer. We tested whether endogenous CD3 chains are rate-limiting for TCR expression and antigen-specific T-cell function. We show that co-transfer of CD3 and TCR genes into primary murine T cells enhanced TCR expression and antigen-specific T-cell function in vitro. Peptide titration experiments showed that T cells expressing introduced CD3 and TCR genes recognized lower concentration of antigen than T cells expressing TCR only. In vivo imaging revealed that TCR+CD3 gene modified T cells infiltrated tumors faster and in larger numbers, which resulted in more rapid tumor elimination compared with T cells modified by TCR only. After tumor clearance, TCR+CD3 engineered T cells persisted in larger numbers than TCR-only T cells and mounted a more effective memory response when rechallenged with antigen. The data demonstrate that provision of additional CD3 molecules is an effective strategy to enhance the avidity, anti-tumor activity and functional memory formation of TCR gene modified T cells in vivo.

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Consequences of Exposure to Ionizing Radiation for Effector T Cell Function In Vivo

Viral Immunology ◽

10.1089/vim.1989.2.69 ◽

1989 ◽

Vol 2 (2) ◽

pp. 69-78 ◽

Cited By ~ 6

Author(s):

B.T. ROUSE ◽

D. HARTLEY ◽

P.C. DOHERTY

Keyword(s):

T Cell ◽

Ionizing Radiation ◽

Cell Function ◽

Effector T Cell ◽

T Cell Function

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Leukemia Related Co-Stimulation / Co-Inhibition Predict T-Cell Attack of Acute Lymphoblastic Leukemia Mediated By Blinatumomab

Blood ◽

10.1182/blood.v126.23.3764.3764 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3764-3764

Author(s):

Tobias Feuchtinger ◽

Judith Feucht ◽

Simone Kayser ◽

David Gorodezki ◽

Michaela Döring ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

Cell Function ◽

Lymphoblastic Leukemia ◽

Surface Expression ◽

Signaling Molecules ◽

T Cell Function ◽

Healthy Donors ◽

Pediatric All

Abstract Refractory B-precursor acute lymphoblastic leukemia (ALL) remains an unsolved therapeutic challenge. Various T-cell immunotherapies are promising options in relapsed/refractory B-ALL, like the CD19/CD3-bispecific T-cell engaging antibody Blinatumomab. Until now it has not been possible to determine critical factors for T-cell attack against leukemia that decide on in vivo response or non-response to treatment. Immune-checkpoint molecules regulate immune escape of malignant cells and antibody blockade of these inhibitory pathways enhances antitumor immune responses. Therefore, we investigated the role of co-stimulatory and co-inhibitory molecules for effector-target cell interactions and influence on T-cell attack against leukemia. CD19+ lymphoblast lines, primary pediatric B-ALL bone marrow blasts (n=10) and physiologic CD19+ CD10+ pre-B bone marrow precursors from healthy bone marrow were screened for surface expression of 20 different co-signaling molecules. Surface expression of PD-L1, PD-1, LAG3, CD40, CD86, CD27, CD70 and HVEM revealed differences in stimulatory and inhibitory profiles of pediatric ALL blasts as compared to physiologic cells. Pediatric ALL patients refractory to Blinatumomab-treatment (n=4) as well as patients with relapsed leukemia (n=7) showed increased expression of PD-L1 on blasts. Expression of exhaustion markers PD-1 and TIM-3 was significantly higher on patients' T cells as compared to healthy donors and is induced by T-cell attack against blasts. Blinatumomab-mediated T-cell function was examined in healthy donors as compared to pediatric patients with ALL through analysis of proliferation and effector function. Significant differences in Blinatumomab-induced T-cell function were found to be target-cell dependent and correlated to expression of co-signaling molecules on target cells. Blockade of inhibitory PD-1-PD-L and CTLA-4-CD80/CD86 interactions could further enhance effector T-cell function of healthy donors and patients whereas blockade of co-stimulatory CD28-CD80/86 interactions resulted in reduced T-cell effector and proliferation potential. Combined treatment with Blinatumomab and PD-1 blocking antibody Pembrolizumab was feasible and induced an anti-leukemic immune response in a 12 year old patient with refractory ALL. In conclusion, we show that regulation of T-cell activation and inhibition by co-signaling molecules guides the efficacy of T-cell attack against ALL. Inhibitory interactions between leukemia-induced checkpoint molecules on T cells and their counterparts on ALL regulate in vivo resistance to T-cell immunotherapy and will guide future therapeutic interventions. Disclosures Off Label Use: Pembrolizumab.

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T cell-dependent immunodepression in vivo in Schistosoma mansoni infected patients

Revista da Sociedade Brasileira de Medicina Tropical ◽

10.1590/s0037-86821990000100005 ◽

1990 ◽

Vol 23 (1) ◽

pp. 27-31 ◽

Cited By ~ 6

Author(s):

Maria Imaculada Muniz-Junqueira ◽

Carlos Eduardo Tosta ◽

Aluizio Prata

Keyword(s):

T Cell ◽

Schistosoma Mansoni ◽

Cell Function ◽

Intracellular Pathogens ◽

Spleen Size ◽

T Cell Function ◽

Intradermal Tests ◽

Hepatosplenic Schistosomiasis

T-cell function was evaluated in 29 patients with either hepatointestinal or hepatosplenic schistosomiasis by intradermal tests to recall antigens. Immunodepression was detected in 26% of the subjects with hepatointestinal schistosomiasis and in 50% of those with the hepatosplenic form. Cellular immunodepression was related to worm load and spleen size. This non specific T-cell immunodepression may represent a serious constraint to the elimination of intracellular pathogens both in hepatosplenic or hepatointestinal schistosomiasis.

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