Transplantation Flashcards
what is autografting?
transfer of graft from one part of the body to another
what is allografting?
transfer of graft from one individual to another of the same species
what is xenografting?
transfer of graft from one individual to another of different species
what is isografting?
transfer of graft between identical twins
what are allo-antigens?
all antigens that differ between individuals of the same species
what do TCRs recognize?
foreign peptides in self-MHC molecules
name 3 different allo-antigens
- major histocompatibility complex (MHC) antigens/ HLA; cause fast and strong rejection because of differences in HLA
- minor histocompatibility complex antigens (miHLA = non-MHC antigens); cause slow and weak graft rejection because of genetic differences in other proteins but same HLA
- blood group antigens
name the 3 characteristics of HLA class I
- HLA-A/B/C
- present on all nucleated cells of the body
- recognized by CD8+ T cells
name the 3 characteristics of HLA class II
- HLA-DP/DQ/DR
- present on APCs and activated CD4+ T cells
- recognized by CD4+ T cells
name 2 types of minor allo-antigens
- all other proteins that differ in amino acid composition between donor and recipient because of genetic mutation/polymorphism, presented by recipient HLA to recipient T cells
- proteins encoded by y-chromosome because of transplantation from man to woman, presented by recipient and donor HLA to recipient T cells
what is direct allo-recognition?
recipient T cell recognizes intact donor HLA on donor APC, is the result of cross-reactivity of TCRs that recognize self MHC molecule + foreign peptide to a foreign MHC molecule + another foreign peptide
what is indirect allo-recognition?
recipient T cells recognizes peptide of donor HLA presented in recipient HLA molecule on recipient APC
what is semi-direct allo-recognition?
recipient APCs acquire intact donor HLA presenting peptides recognized by recipient T cell
name 4 signs of kidney transplant rejection
- rise in creatine
- decreased urine production
- fever, malaise, abdominal pain
- reduced liver function
name the 4 targets for rejection
- ABO blood group system
- HLA
- minor antigens
- injury
what happens after a ABO-incompatible transplantation?
anti-ABO antibodies stick to red blood cells and organ graft resulting in hyperacute rejection (lysis of blood/organ cells)
what are 3 reasons for having pre-existing antibodies against donor HLA (donor reactive antibodies)?
- pregnancy
- blood transfusions
- earlier transplantation
how can donor reactive antibodies be detected before transplantation?
cross-match (complement dependent cytotoxicity) test; expose donor cells to recipient serum and complement, in the presence of DSA donor cells will be lysed
what are the 3 requirements of an organ transplantation?
- ABO system compatible
- negative cross match
- HLA typing
why is tissue injury not compatible for transplantation?
- leads to inflammatory responses/ischemia reperfusion injury
- cardiac death donor; disturbance of blood supply to donor organs
- brain death donor; cytokine storm affecting donor organs
how can ischemia reperfusion be reduced?
machine preservation; oxygen, nutrient, temperature control
name the 4 types of graft rejection
- hyperacute rejection; immediate lysis of donor cells, presence of ABO or donor HLA specific antibodies
- acute rejection; cellular rejection, T cell mediated (rapid rise in creatinine, fluid retention, infiltration of recipient immune cells in graft)
- acute antibody mediated rejection; humoral rejection, B cell mediated (anti-donor HLA antibodies bind to donor cells, activate complement system, lysis of target cells and phagocytosed by macrophages)
- chronic rejection; slow deterioration of kidney function, continuous low level of inflammation and chronic calcineurin inhibitory (CNI) nephrotoxicity, fibrosis in the graft
name 2 treatments for acute cellular rejection
- high doses of methylpredisolone (corticosteroids)
- ATG; anti-thymocyte globulin, depletion of T cells
name 3 treatments for antibody mediated rejection
- plasmapheresis
- IVIg; depleting antibodies
- rituximab; anti-CD20, depleting B cells
what are the 3 histological aspects of a kidney T cell mediated rejection (TCMR)?
- T cells
- tubulointerstitial
- vascular rejection
what are the histological aspects of a kidney antibody mediated rejection?
- antibody; monocytes and NK cells
- microvascular inflammation
- C4d+
- donor specific antigen (DSA)
name the 3 stages of immunosuppression
- induction therapy
- maintenance therapy
- anti-rejection therapy
what is the standard induction therapy for kidney transplantation?
basiliximab, signal 3 blocking antibody and anti-CD25
what are the 3 most important side-effects of immunosuppressive drugs?
- infections
- malignancies (cancer)
- cardiovascular disease
name 3 immunosuppressive drugs used in maintenance therapy
- tacrolimus
- mycophenolate mofetil
- prednisolon
how does prednisolon work?
inhibit mRNA expression
how can infections be prevented before use of immunosuppressives?
- vaccinations before transplantation
- anti-bacterial/viral prophylaxis
- tapering immunosuppression
- life style advice
how can malignancies be prevented before use of immunosuppressives?
- population screening
- tapering immunosuppression
how can cardiovascular disease be prevented before use of immunosuppressives?
- steroid-free regimen
- tapering tacrolimus
why does tacrolimus need therapeutic drug monitoring?
small therapeutic window and prone to infections with other drugs
what are alternative immunosuppressive agents for a CNI-free regimen?
belatacept, iscalimab, mTOR inhibitors
name 3 advantages of cellular therapies
- less side effects
- long term effects
- more specific (antigen-specific)
name 3 immune cell types that can be used for cellular therapy
- myeloid lineage (MDSC, M2, tolerogenic DC)
- mesenchymal stem cells (MSC)
- lymphoid lineage (CD4/8, T/B cells)
what is the function of myeloid regulatory cells?
play a role in tissue homeostasis
what is the function of regulatory macrophages (M2)?
induced by co-stimulation of activated macrophages, produce IL-10
name 3 subtypes of mesenchymal stem cells
- osteoblasts
- adipocytes
- chrondrocytes
peri-capillary localisation
what is the function of MSC?
expression of immunomodulatory factors (IDO; depletion of L-tryptophan to inhibit lymphocyte proliferation and PD-L1; provide inhibitory signal to T cells)
what is the mechanism of regulating immune responses by CD4+ Tregs?
central tolerance; to delete responses to self-antigens
peripheral tolerance; to limit responses to antigens
what is the function of belatacept?
co-stimulation blockade
name 3 new forms of immunosuppression
- anti-IL6
- Imlifidase; eliminates anti-HLA IgG
- CAR T cells
