Levings Application 1

Question 1

MHC protein numbers (2)

Answer 1

• humans have 6 different genes encoding MHC proteins, with 2 copies of each gene
• total of 12 copies

Question 2

MHC class I (2)

Answer 2

• 3 MHC class I proteins
• HLA-A, HLA-B, and HLA-C

Question 3

HLA

Answer 3

• human leukocyte antigen

Question 4

MHC class II (2)

Answer 4

• 3 MHC class II proteins
• HLA-DP, HLA-DQ, HLA-DR

Question 5

how are MHC proteins key for diversity (3)

Answer 5

• many different alleles for each MHC gene
• polymorphism maximizes probability of binding to peptides from pathogens
• particular combination of 12 HLAs we each express defines our tissue type

Question 6

MHC diversity and transplantation

Answer 6

• MHC diversity is why transplanted cells/organs are recognized as non-self

Question 7

what is the mouse version of the human HLA complex

Answer 7

• mouse H-2 complex

Question 8

allorecognition

Answer 8

• the ability of an individual organism to distinguish its own tissues from those of another

Question 9

allorecognition pathways (3)

Answer 9

• direct pathway
• indirect pathway
• semidirect pathway

Question 10

what percentage of recipient T cells participate in direct pathway allorecognition

Answer 10

• 1-7% of T cells participate in direct recognition for any given donor/host pair depending on degree of donor mismatch

Question 11

allorecognition: direct pathway

Answer 11

• donor APC presents MHC-donor antigen complex to the TCR of a recipient T cell

Question 12

allorecognition: direct presentation steps (2)

Answer 12

• donor-derived DCs leave the graft, migrate to LNs, and stimulate naive alloantigen-specific T cells
• activated T cells traffic to graft where they can be restimulated by donor cells expressing MHC and initiate an immune response

Question 13

which form of presentation is important in early allograft responses

Answer 13

• direct pathway

Question 14

allorecognition: indirection pathway

Answer 14

• transplanted antigens are processed and presented on recipient MHC from recipient APC to a recipient T cell

Question 15

allorecognition: semidirect pathway

Answer 15

• transplanted MHC-donor antigen are presented by a recipient APC to a recipient T cells

Question 16

direct allorecognition types (2)

Answer 16

• peptide centric: donor peptide of donor peptide-MHC is recognized
• MHC centric: MHC peptide of donor peptide-MHC is recognized

Question 17

transplants vs normal immune response

Answer 17

• capacity of donor-derived cells to participate
• direct recognition of alloantigens
• high freq. of alloAg specific cells in both naive and memory T cell pool
• lifelong presence of Ag

Question 18

infection in transplantation: 1-12 months after transplant (2)

Answer 18

• maximum immune suppression due to immunosuppressants
• opportunistic infections, relapses, and reactivations

Question 19

infection in transplantation: over 12 months (2)

Answer 19

• late-onset infections
• opportunistic infections and community-acquired infections

Question 20

clinical application of strategies to induce tolerance (2)

Answer 20

• central tolerance strategies (deletion)
• peripheral tolerance strategies (anergy & suppression)

Question 21

clinical application of strategies to induce tolerance: central tolerance

Answer 21

• HSC transplantation to re-set central tolerance

Question 22

clinical application of strategies to induce tolerance: peripheral tolerance (2)

Answer 22

• co-stimulation blockade/modulation
• cell therapy with regulatory immune cells
• in vivo boosting of regulatory immune cells

Question 23

HSC transplantation: autologous transplantation
- benefit
- risks (2)

Answer 23

• benefit: no risk of graft versus host disease
• risk: incomplete ablation of autoreactive cells
• risk: same genetic risk factors in immune cells

Question 24

HSC transplantation: allogeneic transplantation
- benefits (2)
- risk

Answer 24

• benefit: reduced genetic risk of autoimmunity
• benefit: assuming complete reconstitution, no space for autoreactive cells
• risk: graft versus host disease

Question 25

allogeneic

Answer 25

- individuals of the same species who are genetically different and immunologically incompatible

Question 26

autologous

Answer 26

- cell/tissues obtained from same individual

Question 27

graft versus host disease

Answer 27

- T cells of the donated stem cells/bone marrow cells attack the host cells

Question 28

Tregs as cellular therapy to induce transplantation tolerance: Treg sources (2)

Answer 28

- can be taken from patient - can be from third source (blood donation, cord blood, thymus, etc)

Question 29

Tregs as cellular therapy to induce transplantation tolerance (3)

Answer 29

- Tregs taken from sources and undergo in vitro expansion - cell therapy to insert Tregs back into patient - Tregs police immune system, regulate and control immune responses to stop graft rejection and graft vs host disease

Question 30

Treg cell therapies examples (7)

Answer 30

- type 1 & 2 diabetes - MS - rhematoid arthritis - IBD - allergies - allograft rejection - graft versus host disease

Question 31

strategies to block Tregs applications (3)

Answer 31

- cancer - chronic infections - vaccination

Question 32

regulatory cell therapy paper: kidney rejection outcomes

Answer 32

- CTG had slightly lower rate of biopsy confirmed acute rejection compared to RGT

Question 33

regulatory cell therapy paper: infection outcomes

Answer 33

- CTG had lower rate of infection compared to RGT

Question 34

regulatory cell therapy paper: effects on immune cell populations

Answer 34

- RGT patients had major alterations in absolute and relative blood immune cell population composition compared with healthy controls

Question 35

regulatory cell therapy paper: effects on Tregs

Answer 35

- no significant difference in number/proportions of Tregs between groups 60 weeks post-kidney transplant

Question 36

resetting central tolerance: HSCT for solid organ transplant steps (7)

Answer 36

1. conditioning drug regime 2. transplantation of donor BM 3. donor HSC engraftment 4. multilineage chimerism 5. peripheral tolerance (intragraft) 6. peripheral tolerance (secondary lymphoid organs) 7. central tolerance

Question 37

re-setting central tolerance: HSCT for solid organ transplant; thymus (4)

Answer 37

- recipient and donor bone marrow enter thymus - alloreactive T cell from both donor and recipient in thymus - alloreactive recipient and donor T cells negatively selected and die - mature, non-alloreactive T cells escape to blood as a mixed chimera