1.3 transplantation immunology

why does a person with type A blood fail to produce Ab specific for A-antigen? why does a person with type A blood make Ab for B-antigen?

because a person with type A has surface A antigens on it and to be self-reactive it will not make Ab for A-antigen. Both A and B antigens have similar antigens found in gut so that is why a person with type A blood would then make antigens against B (but not A as to not be self-reactive)

• vice versa for type B blood

• type O has no surface antigens so it has Ab for A and B antigens

• type AB has both surface antigens so so it makes no Ab for A and B

define HLA

human leukocyte antigens; cells that identify cell vs non-self

blood type A can receive transfusion from:

A and O

type B can receive transfusion with:

B and O

type AB can receive transfusion with

AB, A, B, and O (universal recipient)

type O can receive transfusion with

O only universal donor

name the four types of grafts:

• autograft

• isograft

• allograft

• xenograft

autograft

donor and recipient same person

isograft (syngeneic graft)

donor and recipient genetically identical (monozygotic twins)

allograft

allogenic graft; donor and recipient genetically different

xenograft

xenogeneic graft; donor and recipient different species

the T cell response against an allograft is very strong, why might this be the case?

MHC (major histo compatibility)! not genetically the same so tissue compatibility is important

two mechanisms by which grafts are recognized by recipient T cells

1. recipient T cells recognize processed donor MHC peptides being represented by recipient’s APCs; “normal mechanism” aka recognition of foreign peptide presented by self-MHC

   1. recipient APC and recipient CD4 T cell

2. recipient T cells directly recognize allogeneic donor MHC molecules on graft APCs; “special”’ many recipient T cells CD8 (MHC Class II) and CD4 (MHC Class II) respond to allo-MHC regardless of peptide

   1. recipient T cells recognize donor APC

   2. strong allogenic MHC response → tissue damage

why would T cell immune response attacking allografts and xenografts be exceptionally powerful?

both CD4+ and CD8+ T cells directly recognize foreign MHC (allo and xeno) without regard to peptide

three methods of allograft rejection

• hyper-acute rejection

• acute rejection

• chronic rejection

minutes or hours after transplant

preformed (b4 transplant) Abs directed at graft

hyper-acute rejection

days to weeks after transplant (10-14 days)

CD8+ (cytotoxic) directed at allogenic HLA of graft

immunosuppressive drugs to stop

acute rejection

months or years after transplant

Ab to allogeneic HLA and T cell inflam (CMI, CD4 especially produce inflam cytokines and even ADCC NK cell attack on graft)

immunosuppressive drugs to slow

chronic rejection

what can acute pre-formed Ab to HLA be due to?

childbirth (anti-father’s HLA)

previous blood transfusion

previous organ. transplant recipient

ABO blood group incompatibility

how to prevent hyperacute rejection:

1. donor and recipient must be matched for ABO blood group (just like transfusion)

2. cross-match: test recipient’s serum Ab to donor

   1. recipient serum + donor lymphocytes + complement =

      1. no lysis: no antidonor Abs

      2. lysis: antidonor Abs

how do you match for a solid organ?

based on number of HLA antigens matching Ab levels of recipient and length of time recipient has been on the wait list; cross-match pre-formed Ab in recipient specific to donor graft

six HLA antigens used to match (six point match), three loci from each parent

ex: 5 point match would be that donor and recipient that only vary by 1/6 HLA alleles

how to prevent solid organ rejection?

• match for ABO blood group compatibility

• test for pre-formed AB (cross-match)

• match HLA

• immunosuppressive drugs

• live donor > cadaveric donor

what is HSC transplantation?

hematopoietic stem cell transplantation: treat intrinsic defects in one or more hematopoietic lineages and mainly to treat blood cancers; induce into blood stream

eliminate pt’s own hem cells with radiation to “make space”

stem cells can be directly obtained from peripheral blood (after treatment with colony stimulating factor, a hormone that releases stem cell from bone marrow) or from umbilical cord blood or from bone marrow

major problem with bone marrow transplantation?

competent T-cells from donor may be transplanted giving rise to graft vs host disease

define graft vs host disease

a reaction of donor T-cells against recipient MHC

• graft must contain live T cells: contaminating T cells from donor can not only clone but recognize MHC in donor and attack

• recipient must immunosuppressed

• donor and recipient must have different HLA types

what creates the severe inflammation characteristic of GVHD?

CD4+ T cells in graft are activated by allogenic molecules and produce a “cytokine storm” that recruits other T cells, macrophages, and NK cells

steps of a GVHD cytokine storm

CD4+ T cells in graft activated by allogeneic HLA

recruitment of other T cells, macrophages, NK cells

cytokine storm

(rash on palms and soles)

three main immunosuppressive drugs for for allografts

key point: allograft recipients receive a cocktail of immunosuppressive drugs that must be taken for life!

• cyclosporine (CsA) and tacrolimus : block IL-2 for T cell prolif, block calcineurin (T cell phosphate)

• sirolimus: block IL-2, does not block calcineurin so lower kidney toxicity

• corticosteroids: anti-inflam, broad immunosupp

dental implant bone grafts

• autografts: best success rates

• allografts (cadaver) xeno (bovine)

what do you need to do to prevent allograft bone from eliciting immune repsonse?

treat tissues so no rejection

• irradiation

• freeze-dry

• acid wash

• chemical treatments

• donors pre-screened for infectious disease

also: review health history, non-invasive exam, consult w PCP (health status, timing, Ab needed?, precaution against bleeding, appropriate meds/dosage)

main point about immunosuppression?

immunosuppressive agents can cause gingival hyperplasia, poor healing and infections; need inflam to heal and get rid of bugs

ex: cyclosporin-induced gingival hyperplasia