Induction of immune tolerance after spinal grafting of human ES-derived neural precursors

Induction of immune tolerance after spinal grafting of human ES-derived neural precursors

Funding Type: 
Transplantation Immunology
Grant Number: 
RM1-01720
Approved funds: 
$1,387,800
Disease Focus: 
Spinal Cord Injury
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
Public Abstract: 
Previous clinical studies have shown that grafting of human fetal brain tissue into the CNS of adult recipients can be associated with long-term (more then 10 years) graft survival even after immunosuppression is terminated. These clinical data represent in part the scientific base for the CNS to be designated as an immune privilege site, i.e., immune response toward grafted cells is much less pronounced. With rapidly advancing cell sorting technologies which permit effective isolation and expansion of neuronal precursors from human embryonic stem cells, these cells are becoming an attractive source for cell replacement therapies. Accordingly, there is great need to develop drug therapies or other therapeutic manipulations which would permit an effective engraftment of such derived cells with only transient or no immunosuppression. Accordingly, the primary goal in our studies is to test engraftment of 3 different neuronal precursors cell lines of human origin once grafted into spinal cord in transiently immunosuppressed minipigs. In addition, because the degree of cell engraftment can differ if cells are grafted into injured CNS tissue, the survival of cells once grafted into previously injured spinal cord will also be tested. Second, we will test the engraftment of neuronal cells generated from pig skin cells (fibroblasts) after genetic reprogramming (i.e., inducible pluripotent stem cells, iPS). Because these cells will be transplanted back to the fibroblast donor, we expect stable and effective engraftment in the absence of immunosuppression. Jointly by testing the above technologies (transient immunosuppression and iPS-derived neural precursors), our goal is to define the optimal neuronal precursor cell line(s) as well as immunosuppressive (or no) treatment which will lead to stable and permanent engraftment of spinally transplanted cells.
Statement of Benefit to California: 
Brain or spinal cord neurodegenerative disorders, including stroke, amyotrophic lateral sclerosis, multiple sclerosis or spinal trauma, affect many Californians. In the absence of a functionally effective cure, the cost of caring for patients with such diseases is high, in addition to a major personal and family impact. Our major goal is to develop therapeutic manipulations which are well tolerated by patients and which will lead to stable survival of previously spinal cord-grafted cells generated from human embryonic stem cells. If successful, this advance can serve as a guidance tool for CNS cell replacement therapies in general as it will define the optimal immune tolerance-inducing protocols. In addition, the development of this type of therapeutic approach (pharmacological or cell-replacement based) in California will serve as an important proof of principle and stimulate the formation of businesses that seek to develop these types of therapies (providing banks of inducible pluripotent stem cells) in California with consequent economic benefit.
Progress Report: 

Year 1

The use of autologous, induced pluripotent stem cell-derived cell lines in replacement therapies holds great promise in future clinical use. No need for immunosuppression, otherwise required to prevent transplanted cell rejection, would represent a substantial advance in the current clinical utilization of cell replacement therapies. In our recently completed studies we have found that autologous porcine iPSC-derived neural precursors (NPCs) grafted back to the donor animal spinal cord in the absence of immunosuppression was associated with a poor cell survival and extensive inflammation at cell-grafted sites. Our data raises immunological concerns on the use of autologous iPS-cell derivatives for future regenerative medicine in humans.

Year 2

The use of autologous, induced pluripotent stem cell-derived cell lines in replacement therapies holds great promise in future clinical use. No need for immunosuppression, otherwise required to prevent transplanted cell rejection, would represent a substantial advance in the current clinical utilization of cell replacement therapies. In our recently completed studies we have found that autologous porcine iPSC-derived neural precursors (NPCs) grafted back to the donor animal spinal cord in the absence of immunosuppression was associated with a poor cell survival and extensive inflammation at cell-grafted sites. In more recent study we have determined that the same cell population of iPS-NPCs survive and mature once grafted spinally in immunosupressed pigs.The mechanism of the immunogenicity of iPS-NPCs is being currently determined.

Year 3

The use of autologous, induced pluripotent stem cell-derived cell lines in replacement therapies holds great promise in future clinical use. No need for immunosuppression, otherwise required to prevent transplanted cell rejection, would represent a substantial advance in the current clinical utilization of cell replacement therapies. In our recently completed studies, we have found that autologous porcine iPSC-derived neural precursors (NPCs) trigger a positive T-cell mediated reaction in vitro and that this response is not present if autologous T-cells are co-cultured with autologous fibroblasts. These data show that the reprogramming step induces a potent immunogenicity and that extensive screening of clonally-derived iPS-NPCs will be needed to identify clones of autologous NPCs with acceptable immunogenicity profile. Identification of differences in gene activity in differentially derived iPS-NPCs is currently in progress.

© 2013 California Institute for Regenerative Medicine