Human T cells upregulate CD69 after coculture with xenogeneic genetically-modified pig mesenchymal stromal cells

Li, Jiang; Andreyev, Oleg; Chen, Man; Marco, Michael R.; Iwase, Hayato; Long, Cassandra; Ayares, David; Shen, Zhongyang; Cooper, David K. C.; Ezzelarab, Mohamed

doi:10.1016/j.cellimm.2013.08.004

Cited by 10 publications

(8 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the immunosuppressive regimens utilized in most of these studies would currently not be clinically applicable (mainly because they included an anti‐CD154mAb), and therefore, present studies are aimed toward reducing the intensity of the regimen and ensuring that all agents administered are approved for clinical use. Genetic manipulation of the pig to increase the resistance of the islets to the primate T‐cell response is a potential option, as is the cotransplantation of islets with mesenchymal stromal cells or Sertoli cells .…”

Section: Cell and Tissue Xenotransplantationmentioning

confidence: 99%

The pathobiology of pig‐to‐primate xenotransplantation: a historical review

Cooper

Ezzelarab

Hara

et al. 2016

Xenotransplantation

Self Cite

126

129

View full text Add to dashboard Cite

The immunologic barriers to successful xenotransplantation are related to the presence of natural anti-pig antibodies in humans and non-human primates that bind to antigens expressed on the transplanted pig organ (the most important of which is galactose-α1,3-galactose [Gal]), and activate the complement cascade, which results in rapid destruction of the graft, a process known as hyperacute rejection. High levels of elicited anti-pig IgG may develop if the adaptive immune response is not prevented by adequate immunosuppressive therapy, resulting in activation and injury of the vascular endothelium. The transplantation of organs and cells from pigs that do not express the important Gal antigen (α1,3-galactosyltransferase gene-knockout [GTKO] pigs) and express one or more human complement-regulatory proteins (hCRP, e.g., CD46, CD55), when combined with an effective costimulation blockade-based immunosuppressive regimen, prevents early antibody-mediated and cellular rejection. However, low levels of anti-non-Gal antibody and innate immune cells and/or platelets may initiate the development of a thrombotic microangiopathy in the graft that may be associated with a consumptive coagulopathy in the recipient. This pathogenic process is accentuated by the dysregulation of the coagulation-anticoagulation systems between pigs and primates. The expression in GTKO/hCRP pigs of a human coagulation-regulatory protein, for example, thrombomodulin, is increasingly being associated with prolonged pig graft survival in non-human primates. Initial clinical trials of islet and corneal xenotransplantation are already underway, and trials of pig kidney or heart transplantation are anticipated within the next few years.

show abstract

Section: Cell and Tissue Xenotransplantationmentioning

confidence: 99%

The pathobiology of pig‐to‐primate xenotransplantation: a historical review

Cooper

Ezzelarab

Hara

et al. 2016

Xenotransplantation

Self Cite

126

129

View full text Add to dashboard Cite

show abstract

“…From the studies summarized in this brief review, and from other studies [12–15], we have concluded that:- (i) isolation of MSCs from genetically-modified pigs is efficient; (ii) expression of surface MSC markers and poor expression of SLA and costimulatory molecules can be demonstrated; (iii) tri-lineage differentiation can be achieved; (iv) pMSCs have low xenoantigenicity and also an inhibitory effect on human T cell xenoresponses; (v) GTKO/CD46 pMSCs downregulate human T cell proliferation as efficiently as hMSCs; and (vi) cell-cell contact appears to be required for the MSCs to have their immunomodulatory effects.…”

Section: Discussionmentioning

confidence: 99%

“…At our own center, we have successfully harvested and cultured MSCs from pig bone marrow and adipose tissue [12–15]. We identified a fibroblast-like morphology of genetically-engineered porcine adipose-derived MSCs (Figure 1).…”

Section: Pig Mesenchymal Stromal Cells (Pmscs)mentioning

confidence: 99%

“…Pig MSCs might have considerable therapeutic potential, particularly in xenotransplantation [12–15], but also possibly in allotransplantation and even autoimmune disease. In regard to xenotransplantation there are several potential advantages of pMSCs:-

In the case of organ or cell transplantation, pMSCs can be obtained from the specific organ- or cell-source donor pig or from an identical (cloned) pig.

…”

Section: Potential Advantages Of Pig Mscs Over Human Mscsmentioning

confidence: 99%

See 1 more Smart Citation

The Potential Role of Genetically-Modified Pig Mesenchymal Stromal Cells in Xenotransplantation

Jiang

Ezzelarab

Ayares³

et al. 2013

Stem Cell Rev and Rep

Self Cite

View full text Add to dashboard Cite

Mesenchymal stromal cells (MSCs) are known to have regenerative, anti-inflammatory, and immunodulatory effects. There are extensive indications that pig MSCs function satisfactorily across species barriers. Pig MSCs might have considerable therapeutic potential, particularly in xenotransplantation, where they have several potential advantages. (i) pMSCs can be obtained from the specific organ- or cell-source donor pig or from an identical (cloned) pig. (ii) They are easy to obtain in large numbers, negating the need for prolonged ex vivo expansion. (iii) They can be obtained from genetically-engineered pigs, and the genetic modification can be related to the therapeutic goal of the MSCs. We have reviewed our own studies on MSCs from genetically-engineered pigs, and summarize them here. We have successfully harvested and cultured MSCs from wild-type and genetically-engineered pig bone marrow and adipose tissue. We have identified several pig (p)MSC surface markers (positive for CD29, CD44, CD73, CD105, CD166, and negative for CD31, CD45), have demonstrated their proliferation and differentiation (into adipocytes, osteoblasts, and chondroblasts), and evaluated their antigenicity and immune suppressive effects on human peripheral blood mononuclear cells and CD4+T cells. They have identical or very similar characteristics to MSCs from other mammals. Genetically-modified pMSCs are significantly less immunogenic than wild-type pMSCs, and downregulate the human T cell response to pig antigens as efficiently as do human MSCs. We hypothesized that pMSCs can immunomodulate human T cells through induction of apoptosis or anergy, or cause T cell phenotype switching with induction of regulatory T cells, but we could find no evidence for these mechanisms. However, pMSCs upregulated the expression of CD69 on human CD4+ and CD8+ T cells, the relevance of which is currently under investigation. We conclude that MSCs from genetically-engineered pigs should continue to be investigated for their immunomodulatory (and regenerative and anti-inflammatory) effects in pig-to-nonhuman primate organ and cell transplantation models.

show abstract

“…Li et al. showed that GT‐KO/CD46 pMSC suppressed both CD4 + and CD8 + human T‐cell proliferation in response to PAEC, associated with a downregulation of granzyme B expression. No induction of CD4 + CD25 + Foxp3 hi regulatory T cells or T‐cell apoptosis was detected.…”

Section: Immunobiologymentioning

confidence: 99%

Xenotransplantation literature update, September–October 2013

Schneider

2013

Xenotransplantation

View full text Add to dashboard Cite

Human T cells upregulate CD69 after coculture with xenogeneic genetically-modified pig mesenchymal stromal cells

Cited by 10 publications

References 48 publications

The pathobiology of pig‐to‐primate xenotransplantation: a historical review

The pathobiology of pig‐to‐primate xenotransplantation: a historical review

The Potential Role of Genetically-Modified Pig Mesenchymal Stromal Cells in Xenotransplantation

Xenotransplantation literature update, September–October 2013

Contact Info

Product

Resources

About