Transplantation

twin

genetically identical

genetically different (MHC molecules) but from the same species

transplantation across species

if a different MHC —> graft rejected

syngeneic graft tolerated

allogeneic: graft rapidly rejected & generation of effector memory T-cells even faster rejection upon second graft

T-cell transfer accelerated rejection from a sensitized donor to a naive recipient —> accelerated rejection

skin graft to minor H antigen incompatible recipient

syngeneic MHC but slow rejection of graft due to mHC

can target some polymorphic antigens

mHC: polymorphism in proteins between individuals, most not known

proteins encoded on the KY

H antigen: graft skin from male to female—> H-antigen not present in females (Y encoded)

mHC/single nucleotide polymorphism/MHC restriction

mHC presented by class 1 or class 2 & are identified during graft rejection

B-cell marker CD19 can be polymorphic

Antibody-mediated graft rejection

Anti-blood group antigens

natural, preformed & induced during a previous transplantation —> graft rapidly rejected

ABO antigens are not just expressed by RBC, also endothelial cells -> attack the graft

ABO matching important

glycosylated proteins (lipid or protein)

O antigen is the common antigen part in A & B other sugars added

A: GalNAc at the end

B: Galactose at the end

match blood group Ag to avoid hyperacute reaction

type A: express antigen A & has Abs against B —> can’t have A or AB, can have A or 0

type B: antigen B & anti-A Abs -> can’t have A or AB, can have B or 0

type AB: antigens A + B, neither antibodies (tolerant to both as both expressed) -> can have any type of blood (universal recipient)

type 0: neither A or B Ag, both Ags -> can only have 0 blood (universal donor)

match blood antigen but still humoral late reaction possible

in beginning subacute early response

production of humoral & cellular immunity against donor HLA for HLA-mismatched situations

Anti-HLA Abs —> chronic rejection

endothelial injury enables immune effectors to enter the wall of the artery & to inflict increasing damage

narrows the lumen of the blood vessel --> chronic inflammation -> tissue remodeling

vessel becomes obstructed, ischemic & fibrotic

can be preformed: cross-reactive Abs, screen serum against donor MHC molecules & find pair with less MHC reactive patient before allogenic transplantation

de novo

MHC class I & class 2

class-I like

receptors on endothelial cells (the main target during the rejection process)

extracellular matrix

intracellular Ag —> AIRE is not acting on myosin (can’t induce expression of all self-antigens in medullary epithelial thymus cells)

heart transplants: 40% Ab-rejection if ABO-matched w/o anti-HLA

most prevalent: more frequent than humoral rejection

direct allorecognition: donor APC migrate to the LN to stimulate alloreactive T-cells, direct killing of grafted cells-> physical distance of graft organ & surrounding circulating T-cells -> ingrafted organ resident DC, migrate to DLN & prime T-cells -> migrate into the graft

indirect: APC present allogeneic peptides, inflammation in the grafted tissues by activation -> recipient macrophages, presentation of peptides by recipient molecules & generation of effector T-cells

different targeted pathways/depletion of immune cells

Ab working on T-cell surface or small molecules penetrating the membrane & targeting intracellular pathways

use Ab to block interaction (recombinant, stabilized form of a receptor

-> soluble CTLA-4 fused to stable part (Fc IgG) & allow dimerization for increased avidity

anti-CD25 Ab: basiliximab -> targets major T-cell growth pathway (bind with high-affinity IL-2R)

anti-CD3 mAB: provide signal 1 without signal 2 -> T-cell anergy (prevents T-cell signaling)

anti CD52: alemtuzumab -> deplete T-cells & other leukocytes before transplantation

anti B7: belatacept (soluble form of highest affinity receptor of costimulatory signals CTLA-4)

cept: molecule (soluble receptor) fused with Fc part of human Ab for increased avidity & stability -> decoy receptor, CTLA-4-Fc fusion protein, prevents generation of co-stimulation via CD28

Ab should have human sequences as much as possible

mouse Ab doesn’t work because anti-mouse Ab response

chimeric Ab: ximab, take away Fc part of mice & replace it with human (not optimal ->still mouse sequences)

humanized Ab: zumab, takes a sequence of hypervariable parts of mice & graft loops on the human backbone

cell cycle: mycophenolate, azathioprine ->inhibit replication & proliferation of activated T-cells, nonspecific immunosuppressive drugs, proliferating cells respond

calcineurin: cyclosporin, tacrolimus -> important for NFAT activation

mTOR: sirolimus, required for differentiation of effector T-cells

for grafting of stem cells irradiate patient to eliminate hematopoietic cells & graft stem cells (not possible in routine process -> source bone marrow)

allogeneic hematopoietic cell transplant contains mature & memory T-cells

some can recognize MHC of a patient

—> graft vs host disease

T-cells circulate in the blood to secondary lymphoid tissues, alloreactive cells interact with DC & proliferate effector CD4 & CD8 T-cells enter host tissues & cause injury

performed only with siblings or fully HLA-matched individuals

minor antigens also implicated in GVH

pigs appear optimal -> similar organ size

natural antibodies against a cell surface sugar (α-Gal) present on cells from other mammalian species

generation of α-Gal KO pigs

emergency approval by a patient uneligible for human heart transplantation & medical devices

transplantation of a heart from genetically modified pigs

total of 10 modifications targeting carbohydrate production including α-Gal & anti-CD40 immunosuppression

live for 2 months

still early stage of xenotransplantation