Lec17 Transplan Immunology Flashcards
Isograft
- transplant to self
- identical twins
- inbred mice
Allograft
- transplant between individuals of same species
- rapid rejection by naive mice/human
- alloimmunity from allloreactive B and T cells
Xenograft
- between species [ex. pig and human]
- rapid rejection by naive mice/human
HLA inheritance
co-dominance because inherited as haplotypes
1 in 4 chance that new sibling will have same HLA
Early inflammation posttransplant
- ischemia and reperfersion and surgical trauma, as cell dies releases lots of antigens and creates damage associated molecular patterns [DAMPS]
- leads to ROS production, complement and TLR stimulation
- neutrophil infiltration ,organ damage
- makes organ more susceptible to immune mediated damage
What are the targets of transplant immunity
- HLA
- minor histocompatibility antigens
What are alloreactive antibodies? How do they develop?
- antibodies that generally recognize exposed region of MHC [HLA] molec
- develop open exposure to alloantigens during pregnancy, blood transfusion, previous transplant, or cross-reactivity
What are alloreactive T cells
- CD4 and CD8 T cells recognize donor MHC
- ability to recognize donor MHC due to chance cross reactivity because recipient T cells were never trained to recognize foreign MHC molec
- by direct or indirect reognition
Whats the difference between direct and indirect recognition of Alloreactive T cells
Direct: T cell binds directly to MHC + peptide presented by donor APC that it recognizes
- rxn involves donor APC/MHC/peptide and recipient T cell
Indirect: Donor antigen taken up by recipient APC and expressed on recipient APC surface for T
- rxn involves donor peptide expressed on recipient APC/MHC and recipient T cell
What is the reason why MHC matched donor/recipient may still have graft rejection?
minor histocompatibility antigens present other than just MHC
Why is male-female transplant difficult?
- males have some proteins made only on Y chromosome
- these are not expressed in female so female does not have tolerance to them
- if woman receives man’s you get immune reaction and rejection
- ex: Smcy, Uty
How do B cells get activated by alloantigen?
- same as normal process
- alloantigen binds BCR, get signal through IgM
How are T cells activated by alloantigen?
- same as normal immune response
- TCR minds MHC for signal 1, CD28/B7 and CD40L/CD40 for signal 2
What is effect of calcineurin blocking on T cell activation in alloantigenic response?
- get block of T cell activation
- calcineurin is part of signalling pathway for stimulation
What is Il-2 role in T cell stimulation?
- released from T cell when activated
- then binds back in autocrine manner and stimulates T cell differentiation and proliferation
What is effect of anti-CD25 in T cell activation?
- anti-CD25 binds and blocks IL-2 from re-binding T cell and causing activation
Effector function of alloantibodies
- anti-HLA antibody binds donor HLA on surface [type II hypersensitivity]
- Fc receptor gamma mediates binding
- get complement cascase activation
- may lose endothelial cells –> thrombosis
How to treat antibody mediated vascularized rejection [acute or hyperacute]
Block complement activtaion
3 Effector mech of T cells
- primed T cels produce cytokines that amplify immune response
- Delayed Type hypersensitivity [IV]: macrophage activation, release cytokins, TNF
- cytotoxicity
What is thought to be pathway for acute cellular rejection?
T cells responding through direct pathway
What are perforin and granzyme B?
cytotoxic molec from CTL that attack allogeneic target cell
Is immunosuppression specific or non-specific?
Non-specific [all cells suppressed]
What type of cells does immunosuppression usually target?
T cells [not B cells]
What is most common side effect of immunosuppresion?
Infection
What are 4 common drugs for immunosuppression
- cyclosporine
- steroids
- sirolimus
- mycophenolate mofetil azathioprine
How do you diagnose acute cellular rejection?
- diagnosed by decrease kidney function, high serum creatinine and renal biospy
What cells are involved in acute cellular rejection
- mononuclear cells
- T cells
- macrophages
- anitbodies can also contribute
How to treat acute cellular rejection? Is it reversible?
By increasing immunosuppresion
YES!
What is effect on kidney of chronic rejection?
- kidney fibrosis, develops after 2-3 yrs
What is thoguht to be cause of late graft failure?
- underimmunosuppresion
What is actively acquire tolerance of foreign cells?
- inject fetal mice with cells from other strain of mouse
- later in adulthood place skin graft from donor onto tolerized recipients
- grafts from cell donor strain last indefinietly
- grafts from another strain rejected
- only works if cells transferred in utero
What are 3 current methods for acquired transplant tolerance
- give bonemarrow cells from donor along with the graft
- block costimulatory [CD28/B7] signals
- expand regulatory T cells and give them to patients
