DNA vaccines and methods for the prevention of transplantation rejection
Inventors
Li, Fengchun • Escher, Alan P.
Assignees
Publication Number
US-9358277-B2
Publication Date
2016-06-07
Expiration Date
2026-05-05
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Abstract
Methods for preventing, delaying the onset of, or treating rejection of an allograft using a DNA vaccine, where the vaccine can comprise a polynucleotide encoding a pro-apoptotic protein, like BAX and/or a polynucleotide encoding an autoantigen or donor antigen, like secreted glutamic acid decarboxylase 55. Administering one of the DNA vaccines to a transplant recipient, as described herein, can induce a donor specific tolerogenic response.
Core Innovation
The invention provides methods for preventing, delaying the onset of, or treating rejection of an allograft through the use of a DNA vaccine. The DNA vaccine comprises one or more plasmids encoding a pro-apoptotic protein (such as BAX) and/or an autoantigen or donor antigen (such as secreted glutamic acid decarboxylase 55, sGAD 55). The vaccine may use different combinations of plasmids, including one with a polynucleotide encoding a pro-apoptotic protein, one with a polynucleotide encoding a donor antigen and CpG motifs that are methylated, or a single plasmid that encodes both components, with CpG motifs methylated to reduce immune stimulation.
The background section identifies the main problem as the limitation of current clinical organ rejection prevention methods, which rely on non-specific immunosuppressants. These treatments fail to prevent chronic rejection and expose patients to higher risks of cancer and infection due to their effect on the immune system. Other methods under exploration, such as co-stimulatory blockade and bone-marrow chimerism, still suffer from late-onset chronic rejection and toxicity, limiting their clinical utility.
This DNA vaccination approach is designed to induce donor-specific tolerogenic responses, thereby increasing graft survival and offering the possibility to reduce dependence on conventional immunosuppressive therapies. The approach utilizes specific methylation techniques to suppress unwanted immune activation caused by bacterial DNA in the plasmids, and administration is performed proximal to the allograft for targeted effect. The method is applicable to various types of transplants, including skin, islet cell transplants, and partial or whole organ transplants.
Claims Coverage
The patent includes three independent method claims, each outlining a distinct inventive feature for the prevention of skin allograft rejection or reducing allograft-induced immune response using DNA vaccines.
Treatment of a skin transplant recipient using a DNA vaccine comprising BAX and methylated sGAD 55 plasmids
A method involving: - Selecting a recipient in need of a skin graft and a donor - Grafting skin tissue from the donor to the recipient - Administering one or more doses of a DNA vaccine, which includes: - A first plasmid with a polynucleotide sequence encoding BAX under the control of a promoter - A second plasmid with a polynucleotide sequence encoding secreted glutamic acid decarboxylase 55 (sGAD 55) under the control of a promoter, and a plurality of CpG motifs, which are methylated to diminish the recipient's immune response to unmethylated CpG motifs - The DNA vaccine is delivered by injection proximal to the transplant site
Promotion of skin allograft survival using a DNA vaccine comprising BAX and methylated sGAD 55 plasmids
A method including: - Selecting a recipient in need of a skin graft and a donor - Grafting skin tissue from the donor to the recipient - Administering one or more doses of a DNA vaccine that contains: - A first plasmid encoding BAX controlled by a promoter - A second plasmid encoding sGAD 55 controlled by a promoter, and including a plurality of methylated CpG motifs - Delivery of the DNA vaccine is by injection near the transplant site
Reduction of allograft-induced immune response using BAX and methylated sGAD 55 DNA vaccine
A method composed of: - Selecting a recipient in need of a skin graft and a donor - Grafting skin tissue from the donor to the recipient - Administering at least one dose of a DNA vaccine, composed of: - A first plasmid encoding BAX with a promoter - A second plasmid encoding sGAD 55 with a promoter and a plurality of CpG motifs that are methylated to decrease immune response to unmethylated CpG motifs - Administration is by injection near the allograft site
The inventive features center on using a DNA vaccine, combining BAX and CpG-methylated sGAD 55 plasmids administered near the allograft site, to treat transplant recipients, promote allograft survival, and reduce allograft-induced immune responses.
Stated Advantages
The invention aims to prevent rejection of allografts without requiring knowledge of donor antigen identity and to reduce the need for traditional immunosuppressants associated with serious long-term side effects.
The DNA vaccine approach induces donor-specific tolerogenic or immunoregulatory responses, thereby increasing allograft survival.
Plasmid methylation diminishes unwanted immune system activation, increasing the specificity and safety of the DNA vaccination.
The method is applicable to multiple types of organ and tissue transplants, broadening clinical utility.
This strategy is easily manipulated at the molecular and cellular level for further improvement.
Documented Applications
Prevention, delay of onset, or treatment of rejection of skin allografts in transplantation.
Promotion of survival of skin allografts in transplant recipients.
Reduction of allograft-induced immune response in skin transplant recipients.
Application to other engrafted tissues or transplanted organs, including islet cell transplants, and partial or whole organ transplants (hearts, lungs, kidneys, and livers).
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