Stem cell immunology Flashcards
What are the 4 types of transplant?
- autologous - from the patient
- synergic - from an genetically identical individual
- allogenic - from the same species
- xenogenic - from a different species
Why is stem cell immunology so important?
- there is a risk of immune rejection unless cells are genetically and epigenetically identical
- need to understand this process and how to avoid it
- are stem cells subject to the same obstacles as solid organ and tissue transplants or do they have their own immune status
What is the most ideal type of stem cell to use in therapy to avoid immune rejection but what is the most feasible?
- ideal would be autologous but this can be expensive and not possible to scale up
- allogenic is the most practical
What differences between donors is a major cause of graft rejection?
- MHC/HLA
- highly polymorphic
- MHC 1 is expressed on all nucleated cells and MHC II on APCs
- mismatches cause rejection
How is the immune mediated tissue rejection mediated in MHC mismatch?
APCs recognise the alloantigens and present them to T cells to activate them. T cells then mediate the destruction of the forgein cells
- t cell memory occurs here - shown in mice
Even if HLA is matched rejection can still occur why?
- antigens on non-HLA proteins
- minor histocaompatibility antigens
- for example antigens on the male Y chromosome being recognised by a female recipient
- rejection occurs more slowlt
Why are embryonic stem cells weakly immunigenic?
- express little or no MHC
- still susceptible to NK killing as they can recognise lack of or altered MHC
- and ESCs will still differentiate into cells that do expressed MHC
How can acceptance of allogenic (ESC) stem cell grafts be promoted?
- injecting mice with antiCD4 and antiCD8 to stop the action of T cells
- doesnt work on solid grafts
- could mean that stem cell grafts are more tolerable?
Expression of which gene is associated with immune privalege and how?
- TGF-B2
- provides a microenvironment conducive to tolerance
- promotes Foxp3+ Treg cells that inhibit T cells by their expression of CTLA-4 and PDL-1
- expressed by ESCs
Are iPSCs less immunogenic than ESCs?
in theory yes as they can be autologous. But iPSCs can be genetically unstable and increased mutation rates could alter antigen expression and cause immune rejection
- iPSCs and their progeny modulate the immune response via IL-10
What happens when iPSCs are directly transplanted?
causes teratoma, necrosis, rejection and T cell infiltration
Rather than direct iPSC transplant what can be done to encorage acceptance?
take iPSCs and differentiate them into the cells required in vitro first then insert the. works in some cells types such as retinal pigment epithelium but not in smooth muscle - different tissues show different tolerances
What immunosuppressive properties can mesenchymal stem cells have?
- multipotent stromal cells expressed in many tissues
- produce immunoregulatory factors in response to inflammatory stimuli
- can suppress activation or function of immune cells via TGF-B, IL-10 and more
- IL-10 is anti-inflammatory and suppresses inflammatory cytokines
- already used to treat autoimmunity and promote bone marrow allograft engraftment
Are mesenchymal stem cells immune privaledged?
some immune privilege but still suffer from immune rejection with genetic and epigenetic mistmatches just slower than in other cell types. MSCs in mice still killed within 48 hours
How could we prevent immune rejection of allogenic stem cells and their progeny?
- create haplobanks of SC lines with genotypes to match most people using rare individuals with homozygous haplotypes that will match multiple people - but so may varieties
- create universal SC lines by genetically modifing them to remove antigens that may alert the immune response - cancer risk
- modulate the immune system during delivery by blocking co-stimulatory pathways with antibodies and fusion proteins or modifying stem cells to express CTLA-4 and PDL-1
