Lipid-mediated gene transfer of viral IL-10 prolongs vascularized cardiac allograft survival by inhibiting donor-specific cellular and humoral immune responses

DeBruyne, Lisa A.; Li, King C.; Chan, Stephanie; Qin, Lihui; Bishop, D. Keith; Bromberg, Jonathan S.

doi:10.1038/sj.gt.3300694

Cited by 73 publications

(36 citation statements)

References 40 publications

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“…Local gene transfer of immunomodulatory cytokines, for example, IL-10 has been shown to prevent graft rejection in various transplant models including the cornea. 13,[15][16][17][18] However, the results presented here indicate that local expression of IL-10 is not sufficient to prevent corneal graft rejection in a full mismatched rat transplant model. Liposome-mediated gene transfer in corneal endothelial cells has been suggested as an interesting technology without inducing immune responses against the transfected cells.…”

Section: Discussioncontrasting

confidence: 40%

“…13,14 Gene transfer and gene therapy leading to IL-10 expression in allogeneic transplants may therefore be a promising therapy to impair effective antigen presentation, reduce graft immunogenicity and inhibit inflammation. Indeed, it has been shown that gene transfer of IL-10 led to prolonged graft survival in different transplant models including the cornea, 13,[15][16][17][18] however, in the latter one, the mechanism of graft prolongation is not clear.…”

Section: Introductionmentioning

confidence: 99%

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Effects of local and systemic viral interleukin-10 gene transfer on corneal allograft survival

et al. 2006

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Section: Discussioncontrasting

confidence: 40%

Section: Introductionmentioning

confidence: 99%

Effects of local and systemic viral interleukin-10 gene transfer on corneal allograft survival

et al. 2006

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“…Gene therapy offers a potential approach to modify the donor organ to modulate the effects of ischemic-reperfusion injury and acute or chronic immune rejection after organ transplantation. Various strategies including direct injection into the myocardium, (1,2) bolus injection into the coronary vasculature (3,4) and in situ warm perfusion, (5) have been used to deliver genes to the transplanted heart. We have developed a cold ex vivo perfusion gene delivery system using adenoviral vectors in both rat (6) and pig (7) heart transplantation models.…”

Section: Introductionmentioning

confidence: 99%

Efficient and Durable Gene Transfer to Transplanted Heart Using Adeno-associated Virus 9 Vector

Miyagi

Rao

Ricci

et al. 2008

The Journal of Heart and Lung Transplantation

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“…Alternatively, it may be possible to circumvent the difficulty of plasma proteases by fusion of the active peptide to a carrier molecule or synthesis of variants resistant to enzymatic degradation. Gene therapy represents another potential solution, because gene transfer of a immunomodulatory MHC class I peptide successfully prolonged cardiac allograft survival in mice (45). In summary, these data demonstrate that a synthetic peptide derived from a conserved region of MHC class II can modulate the immune response in vitro and in vivo through the induction of apoptosis in APC via a caspase-independent mechanism and also T cell hyporesponsiveness.…”

Section: Discussionmentioning

confidence: 89%

A Novel Mechanism for the Immunomodulatory Functions of Class II MHC–Derived Peptides

Murphy¹,

Yu²,

Jiao³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. There is now extensive evidence that synthetic peptides corresponding to linear sequences of MHC molecules are effective immunoregulators, targeting the immune response at many different sites. It has been previously shown that peptides derived from a highly conserved region of MHC class II inhibit proliferation to autoantigen and to both the direct and indirect pathways of allorecognition. This study demonstrates that inhibition of lymphocyte proliferation by nonpolymorphic MHC class II peptides, specifically HLA-DQA1, is sequence-specific and that the inhibitory effect is mediated through the induction of apoptosis in antigen-presenting cells via a caspase-independent mechanism. In addition, T lymphocytes stimulated in the presence of HLA-DQA1 are rendered hyporesponsive to subsequent stimuli. Immunomodulation by HLA-DQA1 is effective in vivo because it prevents both the priming and the effector function of primed allogeneic T cells in a murine DTH model. These observations have important implications for the development of a novel therapy for immune-mediated diseases.The adaptive immune response is dependent on the TCR recognition of a peptide ligand complexed with a MHC molecule on the surface of an antigen-presenting cell. This peptide, and the resultant three-dimensional structure formed by it and the MHC molecule, interacts with the TCR triggering a series of signaling events resulting in T cell activation (1). Critical residues within the peptide form the contact points with the TCR, and variation at one of these sites alone is sufficient to disrupt the interaction or change the T cell response qualitatively, resulting in differential cytokine production, antagonism, or anergy (2). There are now several reports of altered peptide ligands that induce partial activation in vitro, resulting in altered responses to autoantigens and allergens (3,4). In addition, the immunoregulatory effects of altered TCR ligands has been demonstrated in vivo, as exemplified by the prevention of experimental autoimmune encephalomyelitis (5). Such studies require that the specific antigen that elicits the immune response be identified. The pivotal role of peptides in allorecognition has highlighted them as a potential strategy for altering the alloimmune response (6,7). Difficulty in identifying the critical allopeptides recognized by alloreactive T cell clones for each given donor-recipient combination make the use of altered peptide ligands potentially less clinically applicable in transplantation (8).APC are continually presenting antigens on the cell surface that represent molecules within their environment, including self molecules. Indeed, it has been demonstrated that a large percentage of peptides bound to MHC on resting APC are derived from MHC molecules themselves (9). The presence of these MHC-bound peptides derived from conserved regions of the MHC raises questions as to their role in the immune process. One may postulate that they function to stabilize the heterodimer for presentation on the cell surface...

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Lipid-mediated gene transfer of viral IL-10 prolongs vascularized cardiac allograft survival by inhibiting donor-specific cellular and humoral immune responses

Cited by 73 publications

References 40 publications

Effects of local and systemic viral interleukin-10 gene transfer on corneal allograft survival

Effects of local and systemic viral interleukin-10 gene transfer on corneal allograft survival

Efficient and Durable Gene Transfer to Transplanted Heart Using Adeno-associated Virus 9 Vector

A Novel Mechanism for the Immunomodulatory Functions of Class II MHC–Derived Peptides

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