An engineered bifunctional recombinant molecule that regulates humoral and cellular effector functions of the immune system

Pizzolato, Maryellen C.; Fodor, William L.

doi:10.1097/01.tp.0000048492.91165.fc

Transplantation

2003

DOI: 10.1097/01.tp.0000048492.91165.fc

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An engineered bifunctional recombinant molecule that regulates humoral and cellular effector functions of the immune system

Maryellen C. Pizzolato

William L. Fodor²

Abstract: These data illustrate that a single molecule can confer resistance to humoral and cellular immune attack.

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Cited by 3 publications

(9 citation statements)

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“…Spleen cells were isolated from BALB/c mice in DPBS/ these cells) (5). Expression of hCD152-hCD59 is directed to the cell surface where the molecule hCD59 1% FCS after mechanical disruption and one-step ACK lysis (Biofluids, Rockville, MD) and added at a 2:1 ratio is anchored by the glycosyl-phosphatidylinositol linkage (27). The chimeric molecule is flexible enough to allow in complete medium (21).…”

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confidence: 99%

“…Moreover, the assessed using a fusion protein containing the extracelludistinct roles of donor and recipient CD80/CD86 were lar domain of mCD28 and the Fc portion of human IgG1 not determined. Human CD152 (hCD152) binds CD80/ (kindly provided by Dr. Yang Liu, Ohio State Univer-CD86 of various species (23,27). In addition, CD152Ig sity, OH).…”

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confidence: 99%

“…Accordingly, we have expressed on porcine cells a hCD152-hCD59 chimeric molecule that functions in cis T-cell activation by PAEC was assayed using a modified costimulation assay (25). PAEC were seeded to conto prevent the activation of human T cells (27) and NK cells mediated by pCD86 (CD80 was not detected on fluency in a 96-well cluster 24 h prior to coculturing. Spleen cells were isolated from BALB/c mice in DPBS/ these cells) (5).…”

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confidence: 99%

“…Mouse NK cells were isolated from BALB/c SCID Genetic Engineering of Porcine Aortic mice in complete medium as described (10). Briefly, Endothelial Cells each SCID spleen was dissociated and the splenocytes plated in a T25 flask for 2 h at 37°C to remove macroThe hCD152-hCD59-expressing PAEC were generated by retroviral transduction (27). To produce viruses, phages.…”

mentioning

confidence: 99%

“…Porcine aortic endothelial cells (PAEC) provide strong costimulation to human T cells (7,25,27) and trigger hupolybrene (Sigma, St. Louis, MO) method (32) and selected with 5 µg/ml puromycin (Sigma). Viral supernaman NK-cell-mediated cytotoxicity (5) through pCD86.…”

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confidence: 99%

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CD86 Blockade in Genetically Modified Porcine Cells Delays Xenograft Rejection by Inhibiting T-Cell and NK-Cell Activation

et al. 2004

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Porcine xenografts transplanted into primates are rejected in spite of immunosuppression. Identification of the triggering mechanisms and the strategies to overcome them is crucial to achieve long-term graft survival. We hypothesized that porcine CD86 (pCD86) contributes to xenograft rejection by direct activation of host T cells and NK cells. Formerly, we designed the human chimeric molecule hCD152-hCD59 to block pCD86 in cis. To test the efficacy in vivo, we have utilized a pig-to-mouse xenotransplant model. First, we showed that hCD152-hCD59 expression prevents the binding of murine CD28Ig to pCD86 on porcine aortic endothelial cells (PAEC) and dramatically reduces IL-2 secretion by Con A-stimulated mouse splenocytes in coculture. Moreover, IFN-γ secretion by IL-12-stimulated mouse NK cells was averted after coculture with hCD152-hCD59 PAEC. In vivo, control PAEC implanted under the kidney capsule were rapidly rejected (2-4 weeks) in BALB/c and BALB/c SCID mice. Rejection of hCD152-hCD59 PAEC was significantly delayed in both cases. Signs of immune modulation in the hCD152-hCD59-PAEC BALB/c recipients were identified such as early hyporesponsiveness and diminished antibody response. Thus, simply modifying the donor xenogeneic cell can diminish both T cell and NK cell immune responses. We specifically demonstrate that pCD86 contributes to rejection of porcine xenografts.

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confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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CD86 Blockade in Genetically Modified Porcine Cells Delays Xenograft Rejection by Inhibiting T-Cell and NK-Cell Activation

et al. 2004

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Transplantation of Immortalized CD34+ and CD34- Adipose-Derived Stem Cells Improve Cardiac Function and Mitigate Systemic Pro-Inflammatory Responses

et al. 2016

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Adipose-derived stem cells (ADSCs) have the potential to differentiate into various cell lineages and they are easily obtainable from patients, which makes them a promising candidate for cell therapy. However, a drawback is their limited life span during in vitro culture. Therefore, hTERT-immortalized CD34+ and CD34- mouse ADSC lines (mADSCshTERT) tagged with GFP were established. We evaluated the proliferation capacity, multi-differentiation potential, and secretory profiles of CD34+ and CD34- mADSCshTERT in vitro, as well as their effects on cardiac function and systemic inflammation following transplantation into a rat model of acute myocardial infarction (AMI) to assess whether these cells could be used as a novel cell source for regeneration therapy in the cardiovascular field. CD34+ and CD34- mADSCshTERT demonstrated phenotypic characteristics and multi-differentiation potentials similar to those of primary mADSCs. CD34+ mADSCshTERT exhibited a higher proliferation ability compared to CD34- mADSCshTERT, whereas CD34- mADSCshTERT showed a higher osteogenic differentiation potential compared to CD34+ mADSCshTERT. Primary mADSCs, CD34+, and CD34- mADSCshTERT primarily secreted EGF, TGF-β1, IGF-1, IGF-2, MCP-1, and HGFR. CD34+ mADSCshTERT had higher secretion of VEGF and SDF-1 compared to CD34- mADSCshTERT. IL-6 secretion was severely reduced in both CD34+ and CD34- mADSCshTERT compared to primary mADSCs. Transplantation of CD34+ and CD34- mADSCshTERT significantly improved the left ventricular ejection fraction and reduced infarct size compared to AMI-induced rats after 28 days. At 28 days after transplantation, engraftment of CD34+ and CD34- mADSCshTERT was confirmed by positive Y chromosome staining, and differentiation of CD34+ and CD34- mADSCshTERT into endothelial cells was found in the infarcted myocardium. Significant decreases were observed in circulating IL-6 levels in CD34+ and CD34- mADSCshTERT groups compared to the AMI-induced control group. Transplantation of CD34- mADSCshTERT significantly reduced circulating MCP-1 levels compared to the AMI control and CD34+ mADSCshTERT groups. GFP-tagged CD34+ and CD34- mADSCshTERT are valuable resources for cell differentiation studies in vitro as well as for regeneration therapy in vivo.

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TNF, Pig CD86, and VCAM-1 Identified as Potential Targets for Intervention in Xenotransplantation of Pig Chondrocytes

2009

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Xenotransplantation of genetically engineered porcine chondrocytes may benefit many patients who suffer cartilage defects. In this work, we sought to elucidate the molecular bases of the cellular response to xenogeneic cartilage. To this end, we isolated pig costal chondrocytes (PCC) and conducted a series of functional studies. First, we determined by flow cytometry the cell surface expression of multiple immunoregulatory proteins in resting conditions or after treatment with human TNF-α, IL-1α, or IL-1β, which did not induce apoptosis. TNF-α and to a lesser extent IL-1α led to a marked upregulation of SLA I, VCAM-1, and ICAM-1 on PCC. SLA II and E-selectin remained undetectable in all the conditions assayed. Notably, CD86 was constitutively expressed at moderate levels, whereas CD80 and CD40 were barely detected. To assess their function, we next studied the interaction of PCC with human monoblastic U937 and Jurkat T cells. U937 cells adhered to resting and in a greater proportion to cytokine-stimulated PCC. Consistent with its expression pattern, pig VCAM-1 was key, mediating the increased adhesion after cytokine stimulation. We also conducted coculture experiments with U937 and PCC and measured the release of pig and human cytokines. Stimulated PCC secreted IL-6 and IL-8, whereas U937 secreted IL-8 in response to PCC. Finally, coculture of PCC with Jurkat in the presence of PHA led to a marked Jurkat activation as determined by the increase in IL-2 secretion. This process was dramatically reduced by blocking pig CD86. In summary, CD86 and VCAM-1 on pig chondrocytes may be important triggers of the xenogeneic cellular immune response. These molecules together with TNF could be considered potential targets for intervention in order to develop xenogeneic therapies for cartilage repair.

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An engineered bifunctional recombinant molecule that regulates humoral and cellular effector functions of the immune system

Abstract: These data illustrate that a single molecule can confer resistance to humoral and cellular immune attack.

Cited by 3 publications

References 29 publications

CD86 Blockade in Genetically Modified Porcine Cells Delays Xenograft Rejection by Inhibiting T-Cell and NK-Cell Activation

CD86 Blockade in Genetically Modified Porcine Cells Delays Xenograft Rejection by Inhibiting T-Cell and NK-Cell Activation

Transplantation of Immortalized CD34+ and CD34- Adipose-Derived Stem Cells Improve Cardiac Function and Mitigate Systemic Pro-Inflammatory Responses

TNF, Pig CD86, and VCAM-1 Identified as Potential Targets for Intervention in Xenotransplantation of Pig Chondrocytes

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