Porcine Treg depletion with a novel diphtheria toxin-based anti-human CCR4 immunotoxin

Wang, Zhaohui; Navarro-Alvarez, Nalú; Shah, Jigesh A.; Zhang, Huiping; Huang, Qi; Zheng, Qian; Madsen, Joren C.; Sachs, David H.; Huang, Christene A.

doi:10.1016/j.vetimm.2016.10.014

Cited by 10 publications

(3 citation statements)

References 15 publications

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“…A definitive study of the function of Foxp3, in either CD4 or γδ T-cells, to demonstrate their specific actions within veterinary infectious disease remains to be completed. Tools are emerging that will allow an in vivo approach to the manipulation of CD4 + Foxp3 + in some veterinary species already ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

The Chronic Stages of Bovine Fasciola hepatica Are Dominated by CD4 T-Cell Exhaustion

2017

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Fasciola hepatica infection of ruminants leads to non-resolving chronic infection, as patency develops, there is switching to a TGF-β and IL-10 led response. Here, we explore the responses of CD4 T-cells within the major draining lymph nodes. We found minimal expression of Foxp3 within CD4 cells but elevated levels within the γδ (WC1+) population. There is a strong T-cell-intrinsic exhaustion phenotype within the hepatic lymph node (HLN) characterized by a lack of antigen-specific proliferation and cytokine secretion. CD4 T-cells recovered from the HLN had high levels of PD-1 expression and low levels of IL-2 secretion. Exogenous IL-2 partially rescued this defect; when combined with neutralization of IL-10 and TGF-β, full restoration of proliferation, and cytokine production was achieved. Moreover, there is a clear uncoupling of the mechanisms that facilitate this regulation with parasite-specific proliferation and cytokine secretion being governed by independent means. These data would suggest that there is a CD4 T-cell-intrinsic regulation in place early in chronic infection, potentially leading to failure in resistance to reinfection.

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Section: Discussionmentioning

confidence: 99%

The Chronic Stages of Bovine Fasciola hepatica Are Dominated by CD4 T-Cell Exhaustion

2017

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“…Similar to human Tregs, CD4 + Foxp3 + T cells are markers of porcine Tregs, and porcine CD8 + Foxp3 + Tregs have also been identified (Wang et al, 2016). Tregs can exert suppressive functions by prompting secretion of the immunosuppressive cytokines, IL-10 and TGF-b, as well as play important roles in immunotolerance and immune homeostasis (Georgiev et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Cysticercus cellulosae Regulates T-Cell Responses and Interacts With the Host Immune System by Excreting and Secreting Antigens

Fan

Zhang

Ouyang

et al. 2021

Front. Cell. Infect. Microbiol.

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Cysticercus cellulosae (C. cellulosae) excretes and secretes antigens during the parasitic process to regulate the host immune response; however, resulting immune response and cytokine production in the host during infection still remains unclear. We used C. cellulosae crude antigens (CAs) as controls to explore the effect of excretory secretory antigens (ESAs) on T-cell immune responses in piglets. C. cellulosae ESAs induced imbalanced CD4+/CD8+ T-cell proportions, increased the CD4+Foxp3+ and CD8+Foxp3+ T-cell frequencies, and induced lymphocytes to produce interleukin-10, which was mainly attributed to CD4+ and CD4−CD8− T cells. The ESAs also induced Th2-type immune responses. The results showed that the ability of C. cellulosae to escape the host immune attacks and establish a persistent infection may be related to host immune response regulation by the ESAs.

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“…There have also been several porcine recombinant fusion toxins generated, specifically a porcine IL-2 fusion toxin for in vivo depletion of swine CD25+ cells and a porcine CTLA-4 fusion toxin for depletion of antigen presenting cells (APCs) (23). There is also evidence that human therapeutics can cross react with corresponding porcine targets in vivo with great efficacy (24).…”

Section: Swine As a Preclinical Model Of Malignancymentioning

confidence: 99%

Cellular Therapies for the Treatment of Hematological Malignancies; Swine Are an Ideal Preclinical Model

2019

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The absence of clinically relevant large animal tumor models has historically forced experimental cellular therapies for hematological malignancies to translate directly from murine models to clinical trials. However, recent advances highlight swine as an ideal large animal model to demonstrate the safety of murine proof of concept studies prior to their implementation clinically. The availability of the MHC defined MGH miniature swine herd has been key for the development of novel approaches for hematopoietic cell and solid organ transplantation. New spontaneously arising hematological malignancies in these swine, specifically myeloid leukemias and B cell lymphomas, resemble human malignancies, which has allowed for development of immortalized tumor cell lines and has implications for the development of a large animal transplantable tumor model. The novel development of a SCID swine model has further advanced the field of large animal cancer models, allowing for engraftment of human tumor cells in a large animal model. Here, we will highlight the advantages of the swine pre-clinical model for the study of hematological malignancies. Further, we will discuss our experience utilizing spontaneously arising tumors in MGH swine to create a transplantable tumor model, describe the potential of the immunodeficient swine model, and highlight several novel cellular and biological therapies for the treatment of hematological malignancies in swine as a large animal pre-clinical bridge.

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Porcine Treg depletion with a novel diphtheria toxin-based anti-human CCR4 immunotoxin

Cited by 10 publications

References 15 publications

The Chronic Stages of Bovine Fasciola hepatica Are Dominated by CD4 T-Cell Exhaustion

The Chronic Stages of Bovine Fasciola hepatica Are Dominated by CD4 T-Cell Exhaustion

Cysticercus cellulosae Regulates T-Cell Responses and Interacts With the Host Immune System by Excreting and Secreting Antigens

Cellular Therapies for the Treatment of Hematological Malignancies; Swine Are an Ideal Preclinical Model

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