Lecture 23: Transplant Immunology

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Although drugs can help, what is the main determinant of overall graft acceptance/rejection rates?

# of MHC differences the more MHC differences = the harder it is to block or control T cell responses to the donor tissue

Describe the outcome of the following 3 scenarios: a. Self MHC:Foreign peptide with normal TCR: b. Nonself MHC:foreign peptide with normal TCR: c. Nonself MHC:foreign peptide with allogenic TCR:

- normal recognition (tolerant of self-peptides) - foreign MHC recognized w high affinity - foreign peptide recognized w high affinity

Roughly what percent of your T cells are alloreactive?

1-10% of ALL T cells are alloreactive for any given MHC/donor

Females for the most part cannot receive grafts from males due to X/Y incompatibility. Why then, don't mothers reject male fetuses? Give 3 reasons:

1. blocks T cell access 2. indoleamine deoxygenase (degrades W = no protein synthesis) 3. causes anergy in T cells *usually not enough "natural" ABO Ab to cause disease

Consider a skin graft from donor person A to recipient person B: 1. Where are major H antigens found? 2. What cells (and who's cells) are recognizing the major H antigens? 3. What are minor H antigens in this scenario? 4. What/who's cells present them? 5. What process is required for minor H antigen recognition?

1. on donor cells 2. self T cells, pro APC, or other donor cells 3. donor epitopes 4. self-MHC 5. cross-presentation

Give an example of an allogeneic transplant. Xenogeneic transplant.

A = random human -> random human *unrelated! X = pig (porcine) -> human

What are allospecific T cells and how are they different from the rest of your T cells? (Hint: What 2 things may they recognize that normal T cells do not?)

Allospecific T cells can recognize foreign MHC (more common) or foreign peptides (less common) with high avidity (binding strength)

Define the following terms: a. Autologous: b. Syngeneic:c. Congeneic: d. Allogeneic: e. Xenogeneic: f. Orthotopic: g. Heterotopic:

Autologous: own cells/organs Syngeneic: genetically ID Congeneic: very closely related (differ @ 1 locus) ie. siblings Allogeneic: same species but unrelated Xenogeneic: different species Orthotopic: to normal site Heterotopic: to abnormal site

How can a patient with cancer actually benefit from GVHD (then referred to as graft versus leukemia GVL)?

BM has mature T cells that recognize tumor (allogeneic) that are otherwise there due to chemo/irradiation

Give an example of an orthotopic transplant. Heterotopic transplant.

O = heart -> heart area (L upper chest) H = pancreas -> folded under liver

Describe the priming and then response of allogeneic T cell responses.

P = donor DC migrate to LN + recognized by T cells (transplant inflamm. = DAMP signals for T cell activation) R = effector cells primed in LN migrate back to transplanted tissues to mediate rejection

Which cells are (mainly) responsible for the above ^?

T cells

Which of the above transplant(s) usually results in the most success? Least success?

autologous; xenogeneic

How can we (theoretically) reduce GVHD other than by using drugs?

don't want exactly ID donor/rec. + don't want TOTALLY unrelated (GRAPH!!!)

What is GVHD?

donor cells killing self cells too *works on fast dividing tissue cells like hair/nails

What is GVL/GVT?

donor cells killing the tumor

What do these genes (in tunicates) resemble in more developed animals?

fester/uncle fester = NK receptor fuHC = MHC

What system determines tissue compatibility in tunicates?

fester/uncle fester recognition of fuHC probably initiates fusion

Raftos and Weissman's research with tunicates revealed insight into transplant immunology. However, tunicates do NOT have lymphocytes. So how were the transplanted tissues being rejected?

fuHC genes (highly polymorphic)

What happens if two tunicates have compatible fuHC and they come into contact? ________________ What about if they have incompatible fuHC?

fusion rejection

Explain the goal of "mixed chimeras" in reducing GVHD.

generate Tregs: take recipient CD4 T cells and activate w cytokines, Ag has alloreactive MHC = get alloreactive Tregs that can now respond to allogeneic MHC when Tregs are put into the recipient

What is the main treatment to mediate graft rejection? How do these drugs generally work?

immunosuppressive drugs: block T cell prolif./function and cytokine production

Which type of histocompatibility (major/minor) results in a very strong MLR response and which results in a weaker MLR response?

major = +++MLR (stronger signal) - b/c stronger response minor = +/- MLR (weaker signal)

Which results in acute (fast) rejection and which results in delayed rejection: Minor histocompatibility: Major histocompatibility:

minor = delayed (fewer cells spec. for minorMHC + initial steps to go through) major = fast (skips initial steps)

What is a mixed lymphocyte reaction (MLR)?

mix lymph with irradiated donor cells (MHCa x MHCb-irr)

Do allogenic T cell:MHC interactions require co-stimulation (generally)?

no, their high avidity interactions can overcome requirements for costimulation, cytokines, etc.

Give an example of non-T cell mediated graft rejection.

pre-existing Ab "natural" ex/ ABO blood group Ag or tissue-specific Ag

What are minor histocompatibility antigens? (Hint: How are they different from Major histocompatibility antigens?)

presented on self-MHC; require cross-presentation (unlike MHC) - they are donor epitopes

Explain what would happen if an MHCa mouse graft was given to an MHCb mouse. _______________ What would happen if you gave a second MHCa mouse graft to the same MHCb mouse?

rejected rapidly (1st-set rejection) accelerated (2nd-set rejection)

Explain how antibodies can lead to hyper acute rejection. (Hint: Is the graft death really immune mediated?)

when already made Ab response and get 2nd infusion = faster rejection (b/c Ab don't need to prolif. and aren't cells therefore they're already IN circulation!


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