Transplantation Flashcards
What does MHC stand for an why?
Major Histocompatibility Complex → tissue histocompatibility allows for transfer without rejection
*MHC match required for graft
MHC-II = 2 letters → HLA-DP/DQ/DR for humans and H-2 IA/IE for mice
MHC-I = 1 letter → HLA-A/B/C for humans and H-2K/D/L
What is transplantation?
What is the major difficulty to a successful transplantation?
The act of transferring cells, tissues, or organs from one site to another or from one individual to another is now an important medical therapy
Adaptive immune responses to the grafted tissues are the major difficulty to successful transplantation
Rejection is caused by immune responses to alloantigens on the graft
What is the definition of Autograft?
Self tissue transferred from one body site to another
ex: skin graft for severe burns
What is the definition of Isograft?
Tissue transferred between genetically identical individuals Ex: twins, inbred mice
- Donor & recipient are syngeneic
What is the definition of Allograft?
Tissue transferred between genetically different members of the same species
- different human individuals, between mouse strains = are allogeneic
What is the definition of Xenograft?
Tissue transferred between different species
What are the different types of unsuccessful transplantation?
- Graft rejection: recognition of graft as foreign
- Hyperacute
- Acute
- Chronic
*Recipient makes immune response against donor - Graft vs host disease (GVHD): graft recipient as foreign
*Donor graft makes response against recipient
- Only in bone marrow transplants
What is hyperacute transplant rejection?
- Most intense graft rejection ~24 hrs
- Pre-existing antibodies → Ag-Ab complexes → complement activation → will result in rapid Ab-mediated lysis of incompatible donor cells (+ neutrophil attraction)
Often seen in ABO blood graft in incompatible groups (match ABO groups)
Other case:
Pre-formed antibodies against non-self HLA can lead to rapid rejection
- Check for anti-donor HLA antibodies: cross- matching
- In the case of prior unsuccessful graft → Abs where made and memory cells remain against the graft MHC or other proteins → 2nd graft leads to hyperacute transplant rejection
What is acute transplant rejection?
- Begins 7-10 days after graft transplantation, full rejection by 10-14 days (slower kinetics because have to generate T cells by clonal expansion)
- Mediated by T cells → both CD4 and CD8 T cells involved
Similar to infection:
Graft → Re-vascularization → drainage of Ags to local dLN → priming of T cells → Cellular infiltration + effector T cell response → thrombosis and necrosis
What is seen in T cell depletions (by injection of monoclonal Abs) in context of acute transplant rejection?
Anti-CD8 → no difference with control (still get rejection ~ 14 days)
Anti-CD4 → Significant prolongation of the graft
*Need CD4 T cells to give CD8 T cells help and CD4 T cells can also be cytotoxic in that context (removing CD4 dampens a lot the CD8 T cell response as well)
Anti-CD8 + Anti-CD4 → survival of the graft up to 60 days
What happens when you generate allogeneic T cells to MHC-a in MHC-b mouse and then transfer the T cells to a naïve MHC-b mouse given graft from MHC-a?
Graft 1: MHC-a → MHC-b
Transfer allogeneic T cells to MHC-a into naïve MHC-b
Graft 2: MHC-a → naïve MHC-b
Will you get skin graft rejection in a H2b nude mouse?
T cells derived from an allograft-primed mouse can transfer second-set allograft rejection to an unprimed syngeneic recipient
Graft 1: MHC-a → MHC-b → acute transplant rejection (necrosis)
Transfer allogeneic T cells to MHC-a into naïve MHC-b
Graft 2: MHC-a → naïve MHC-b → hyperacute transplant rejection (necrosis)
Nude mice have no thymus → no T cells → graft would be accepted because nothing to mediate the rejection response
What is acute transplant rejection in the case of formation of MINOR histocompatibility antigens?
MHC-a → MHC-a, but still get slow (~60 days) graft rejection
- Same MHC allele, but other minor proteins might be seen as foreign
- Even complete MHC matching does not ensure graft survival
- Polymorphic proteins will be digested by proteasomes within the cell and displayed by MHC-I on cell surface. If the peptide differs from ‘self’ then can generate a T cell response
- Donor & recipient differ at other (non MHC) loci
- Takes longer to reject the graft, but will ultimately still destroy graft (takes time for the protein to be digested and presented on MHC-I)
What is an example of non-MHC situation that can lead to slow acute transplant rejection
Male graft → Woman even if MHC matches, women are not tolerized to proteins encoded for on the Y chromosome
Woman graft → Man is fine because men have an X chromosome
What are 2 ways to get antigen presentation in the case of acute transplant rejection?
Direct allorecognition: the “passenger leukocytes” in the transplanted organ includes DCs which can present antigen to T cells of the recipient
– supporting this idea: depleting DC from grafted tissue can prolong graft survival
– often involved in acute graft rejection
Indirect allorecognition: uptake of allogeneic proteins by recipient antigen presenting cells and presentation to T cells by recipient’s MHC
- peptides from the foreign MHC taken up and presented
- minor histocompatibility antigens
- often these responses lead to antibody responses being generated: alloantibodies
- drainage of antigen to local dLN → antigen uptake by lymph nodes resident DCs → digest antigen and present to T cells → germinal center, follicular T cells, etc.
What are different targets to prevent graft rejection?
- Anti-CD25 antibody preventing IL2 signaling (basiliximab)
- Activation of mTOR to block effector T cell differentiation (sirolimus)
- Depletion of T cells via anti-CD52 antibody (alemtuzumab)
- Prevention of NFAT translocation to the nucleus (cyclosporin A, tacrolimus)
- Inhibition of T cell replication (mycophenolate, azathioprine)
- Blocking co-stimulation (belatacept: CTLA4-Fc fusion)
*drugs ending with mab = monoclonal Ab
- What is a potential off-target effect of blocking anti-CD25 antibody to prevent graft rejection?
- What is a potential off-target effect of depleting T cells via anti-CD52 Ab?
- It would also block regulatory t cells → break tolerance at some sites
- Immuno-deficiency because no Tregs
Why might blocking co-stimulation (belatacept: CTLA-Fc fusion) be better than using the anti-CD25 or cyclosporin A?
Cyclosporin A → prevention of NFAT translocation to the nucleus → general immunosuppression
anti-CD25 → preventing IL2 signaling
Blocking co-stimulation leads to T cells not being able to be fully activated and becoming anergic which prevents graft rejection
*belatacept block CD28-mediated co-stimulation
It allows to preserve the Treg repertoire, a bit more selective
Which grafts are accepted vs rejected?
Donor is always Balb/c
Recipients:
a) C3H
b) Rat
c) Nude mouse
d) C3H, had previous Balb/c graft
e) C3H, had previous C57Bl/6 graft
f) Balb/c
*Assume different strains have different MHC haplotypes
Donor is always Balb/c
a) C3H → rejection, First set rejection (12-14 days)
b) Rat → rejection (MHC and other genomic mismatches, FSR)
c) Nude mouse → Acceptance (no T cells)
d) C3H, had previous Balb/c graft → rejection, SSR (6 days)
e) C3H, had previous C57Bl/6 graft → rejection, FSR
f) Balb/c → acceptance
Which grafts are accepted vs rejected?
a) D = Balb/c, R = (Balb/c x C3H)F1
b) D = Balb/c, R = (C3H x C57Bl/6)F1
c) D = (Balb/c x C3H)F1, R = Balb/c
d) D = (Balb/c x C3H)F1, R = Balb/c, had previous F1 graft
*Assume different strains have different MHC haplotypes
a) D = Balb/c, R = (Balb/c x C3H)F1 → acceptance (MHC codominance)
b) D = Balb/c, R = (C3H x C57Bl/6)F1 → rejection, FSR (12-14 days)
c) D = (Balb/c x C3H)F1, R = Balb/c → rejection (MHC mismatch of C3H, FSR)
d) D = (Balb/c x C3H)F1, R = Balb/c, had previous F1 graft → rejection (SSR, 6 days)
True or False?
a) Second set rejection is a manifestation of immunologic memory
b) Acute rejection is mediated by preexisting host antibodies specific for antigens on the grafted tissue
c) Host dendritic cells can migrate into grafted tissue and act as APCs
d) All allografts between individuals with identical HLA haplotypes will be accepted
e) Cytokines produced by host T helper cells activated in response to alloantigens play a major role in graft rejection
a) Second set rejection is a manifestation of immunologic memory → TRUE
b) Acute rejection is mediated by preexisting host antibodies specific for antigens on the grafted tissue → FALSE (hyperacute)
c) Host dendritic cells can migrate into grafted tissue and act as APCs → TRUE (direct presentation)
d) All allografts between individuals with identical HLA haplotypes will be accepted → FALSE (minor histocompatibility antigens/other proteins)
e) Cytokines produced by host T helper cells activated in response to alloantigens play a major role in graft rejection → TRUE (blocking some cytokines will cause slower graft rejection)
What is chronic transplant rejection?
- Late failure of a transplanted organ – years later
- Not well understood what the cause is: specific immune alloreactivity, non-immune injury or both
- Irreversible & progressive, leading to failure of organ
Often major component is chronic allograft vasculopathy → concentric arteriosclerosis of graft blood vessels:
- Vasculature starts becoming dammaged overtime, specifically in heart and kidney grafts → die off of tissue
- Can get recurring subclinical acute rejection events more or less controlling it (growing dammage overtime)
- Can get recurrence of the pathology that initially lead to the transplant dammaging the tissue
What is graft-vs-host rejection?
Converse of graft rejection can occur when the grafted tissue is bone marrow
Mature donor T cells in the hematopoietic stem cell transplant recognize the recipient tissue as foreign, resulting in inflammatory response in multiple tissues (multi-organ failure)
- Espacially in the case of HLA mismatch (very important for BM transplants)
- Memory T cells are depleted from bone marrow before transplant
What explains feto-maternal tolerance?
physiological “transplant” with no rejection because lots of tolerance mechanisms are in place
- Lots of Tregs
- Lots of control even if exchange between bloods
- Could lead to death of the fetus
How frequent are alloreactive T cells in our repertoire?
Why is this % so high?
Expose T cells to MHC alleles from someone else → Mixed lymphcyte reaction:
Measures the immune response of T cells when they encounter lymphocytes from a different person
~ 1-10% of all T cells will respond to stimulation by cells from another unrelated member of the same species (alloreaction) MHC mismatch
Very high % of alloreactive T cells:
- Positive selection for T cells binding MHC + high cross-reactivity
- TCRs have evolved to bind MHC
