Transplantation - Denzin 4/11/16 Flashcards
major hurdle to successful transplantation
recognition and rejection of transplanted tissue/organ by host immune system
- immunosuppression and immune tolerance strategies are used to try to make transplants successful
- difficulty/success varies
- organ variation: liver is easier, cornea rarely rejected, skin v hard to be tolerized
- individual variation
transplatation terms
- autologous
- syngeneic
- allogeneic
- xenogeneic
- autologous: self donor
- syngeneic: identical twin donor
- allogeneic: another human donor (not twin)
- xenogeneic: diff species donor
first-set and second-set allograft rejection
first-set rejection
- tissue is grafted → revascularized (3-7d) → vascularization delivers immune cells, cellular infiltration occurs (7-10d)→ graft thrombosis/necrosis (10-14d)
second-set rejection : second time through, same thing happens, but faster
- tissue is grafted → vascularization delivers immune cells, cellular infiltration occurs (3-4d)→ graft thrombosis/necrosis (5-6d)
SHOWS THAT THERE IS SPECIFICITY AND MEMORY AGAINST A DONOR ONCE TISSUE IS REJECTED
evidence that graft rejection is an immune response
evidence → conclusion
- rejection shows specificity and memory → adaptive immunity is at work
- ability to rapidly reject can be transferred from a sensitized individual to a naive one via lymphocyes → rejection mediated by lymphocytes
- depletion/inactivation of T lymphocytes by drugs/antibodies reduces graft rejection → rejection requires T lymphocytes
what we see: allogeneic and xenogeneic grafts are always rejected by hosts with healthy immune system
allo/xeno terminology
- allograft, xenograft
- alloantigens, xenoantigens
- alloreactive, xenoreactive
- allograft, xenograft: allogeneic graft, xenogeneic graft
- alloantigens, xenoantigens: antigens that are the targets of rejection response
- alloreactive, xenoreactive: antibodies and T cells that react against allo/xenoantigens
role of MHC in transplant rejection
MHC encodes antigens that dominate transplant rejection
- MHC molecules are the key antigens of allografts that are targeted in rejection
- major histocompatibility antigens are coded for by many genes (complex locus) → encodes MHC I molecules and MHC II molecules
- 6 MHC I alleles [HLA-A, -B, -C x 2parents]
- at least 6 MHC II alleles [HLA-DQ, -DP x 2parents; HLA-DR x 1-2 from each parents]
- recall: MHC alleles are super-polymorphic
MHC molecules look remarkably similar
- recall: T cells are positively selected based on ability to recognize self antigen (a little, but not too much)
- in a transplant, some T cells might recognize the allogenieic MHC as foreign MHC-peptide and attack → immunological cross reaction
allogeneic T cell response is strong
what are some factors that contribute to the strength of the allogeneic T cell response?
- many clones of T cells might cross react with allogeneic MHC if it looks like the complex they are sensitized to
- negative selection (central tolerance) in the thymus selects against T cells that bind to self antigen with high avidity…doesn’t address possibility of TCR having high affinity for allogeneic MHC
- wayyyyy more ligand to available to be recognized as foreign in a graft than in an infection
minor histocompatibility antigens
another group of polymorphic antigens contributing to graft rejection
- mostly allelic forms of normal cellular proteins that differ between donor and recipient
how does an immune response against a transplantation happen?
recall: naive T cell activation is mediated primarily by DCs
- maintains specificity of the immune response - not just any cell can set it off
- buuuuut not all grafts contain DCs!
instead, two pathways:
1. direct recognition
2. indirect recognition
pathways mediating initiation of immune response against a transplant
1. direct recognition/direct presentation of alloantigen
- in transplanted tissues containing DCs, DCs migrate out of graft into lymph nodes → DCs present antigens to host T cells + costimulate → generation of alloreactive T cells that attack graft cells
- only pathway for generation of CTLs that directly lyse graft cells
- indirect recognition/indirect presentation of alloantigen
- HOST DCs ingest graft MHC → donor alloantigens/MHC are presented on DCs by self MHC
- CD4-mediated response
- wouldnt activate CTLs because they’d be specific for recognizing donorMHC-selfMHCI complex! wouldn’t see that in the graft.
- alloreactive CD4 T cells and ab would enter the graft, opsonize, produce cytokines, cause infl, and injure the graft tissue (DCs costimulate)
how do DCs provide costimulation in rejection pathways?
not sure, but do know that costim signals on APCs require innate immune response…
possible explanation: graft cells undergo necrosis → substances released activate APC via innate immune mechs
how do antibodies contribute to immune organ rejection pathway?
recipient B cells recognize donor antigen, process and present it to CD4 cells → leads to B cell activation → antibody production!
3 types of immune mechanisms of graft rejection
- hyperacute
- acute
- chronic
classified based on clinical, pathological features
hyperacute graft rejection
occurs within minutes
mediated by circulating antibodies that exist in host even before donor tissue is transplanted
- could be due to previous pregnancy, organ transplant, blood transfusion
- v uncommon due to cross-matching to make sure donor and recipient match blood types and don’t contain reactive Abs to the other
acute graft rejection
occurs within days-weeks
mediated by T cells and by antibodies specific for graft alloantigens
- CD4 cells secreting cytokines and causing inflammation to damage the graft
- CTLs directly attacking graft
- T cells and abs might also attack graft vessels, leading to vascular disease
current immunosuppression therapy: aims to block activation of alloreactive T cells → prevent/reduce acute rejection
chronic rejection
occurs in months-yrs
fibrosis of graft, gradual narrowing of graft blood vessels (graft arteriosclerosis)
- T cells react against graft alloantigents → production of cytokines → stimulate proliferation of fibroblasts and vsm cells in graft
- abs also contribute
tx: has improved, but chronic rejection is still refractory to most therapy → principle cause of graft failure
prevention and treatment of graft rejection
IMMUNOSUPPRESSION
- drugs are designed to prevent T cell activation and effector functions
key to remember: drugs don’t enact immunosuppression in a way specific to organ rejection → pts become susceptible to infection (esp intracellular microbes) + increased incidence of cancer (lower immunosurveillance)
MATCHING DONOR/RECIPIENT MHC
- esp important for bone marrow transplant and renal allographs
relatively speaking, matching less imp today due to effectiveness of immunosuppressive drugs
- now, number of donor organs is the limiting factor → lots of looks into xenogenics
- thus far, xenogeneic organs are immunogenic and usually rejected via hyperacute mech
cyclosporin
transplant drug
TCR blocker
acts at level of calcineurin to prevent activation of tf NFAT
rapamycin
transplant drug
acts downstream of IL2-receptor to block proliferation
hematopoeitic stem cell transplantation
increasingly used to…
- correct hematopoeitic defects
- restore bone marrow damaged by irradiation, chemo
- treat leukemia
HSCs injected into recipient → homing to bone marrow
- issue: recipient’s bone marrow is ablated before hand = destroying that person’s immune system
- another issue: if mature allogenic T cells are transplanted with the HSCs, T cells can attack host tissues → Graft v Host disease
GvHD
Graft versus Host disease
[bone marrow transplantation]
CTLs in transplant attempt to destroy host
- usually not life threatening bc the host’s immune system also reacts against graft
- HOWEVER, if host lacks immune system (say…bc you knocked it out…), it can be life threatening
- often the case in transplant after anti-cancer treatment (graft usually has more T cells than host in this case bc chemo knocked all the host’s out)
GvHD is reduced by depletion of immunocompetent T cells from transplanted marrow
also look out for GvHD in whole blood transfusions to immunosuppressed/deficient people!
