Transplant Rejection

Major Histocompatibility complex (MHC)

• Also known as Human Leukocyte Antigen (HLA)

• They are encoded cell surface molecules that are specialized to present antigenic peptide to T-cells.

• Controlled by Genes Located on Chromosome 6.

Role of MHC

• T-lymphocytes recognize antigens that are presented by MHC.

• Two types of MHC (class I and class II) are recognized by different T cells.– CTL recognizes Ag peptide in MHC class I– T-helper recognizes Ag peptide in MHC class II

Antigens

• Are proteins that have been clipped into smaller subunits.

• Made from:– Viral– Bacterial– Tissues

• Used to make antibodies.

Structure of MHC class I

• Two polypeptide chains– Long α chain and short β

• Made up of 350 a.a• 57 kDa

[purple, turquoise, green] = α region[pink] = β region

Antigen Binding Cleft (MHC I)• Cleft is composed of:

– walls made up of both α helical sections

– floor made up of β sheets • Residues lining floor are

most polymorphic– They are the most different

from person to person• Contains Tyrosine, used

for anchoring the antigen• Groove binds peptides ~10

AA longNon-Covalent Interactions occur

Structure of MHC class II

• Two polypeptide chains– α and β– approx equal length

• α = 230 a.a• Β = 240 a.a

• Each segment ~ 30 kDa

Antigen Binding Cleft (MHC II)

• Groove composed of – α helix walls– β pleated floor

• Floor residues are polymorphic

• In place of Tyrosine, there are more Valine and glycine.

• Groove binds peptides ~15 - 20 AA long

• Each MHC has ONE antigen binding site– Each MHC can bind several different antigens but

only “ONE” at a time.• Peptide must bind with individual’s MHC to

induce immune response• No “Conformational” change is induced

T-cell

Antigen

MHC Complex

Allograft Rejection OverviewAntigen Binds to

the MHC Complex I or II

T-cells dock and an immune response

is triggered

T-cell proliferationT-cells attack transplanted tissue

Organ Tissue Lyses and Dies

Rejection through MHC I

• T-Cell binds to the MHC

Binding

• Stimulates the production of

“CD-8+”, Cytotoxic T-cells

Triggering• Apoptosis

Cell Death

Rejection through MHC II

• T-cell binds to the MHC Class II Comlex.

Binding

• T-cells activate.• T-cells multiply

themselves

Triggering • Inflammation response occurs

• Activation of B cells.• Attracts other

lymphocytes to area.

Cell Attack

Rejection Effects

• Hyperacute – within minutes• Acute – within hours to days• Chronic – episode occur overtime

Corticosteroids

• Used first in the drug treatment.

• Exerts negative regulatory effect on the cytokine gene expression on the T-cell.

• Causes Lyphocytopenia, causing the lysis of immature T-cells

• Impedes inflammatory response by eliminating vasoactive and chemo-attractant substances.

Calcineurin Inhibitors

Prevents calcineurin pathway.

Increased affinity causes immunophilins to bind to calcineurin.

Cyclosporine or Tacrolimus binds to intracellular immunophilins.

Anitmetabolites• Causes metabolic dysfunction

in the T-cell.• Inhibits:

– Purine Metabolism– Nucleotide Synthesis

• Inhibition of DNA synthesis

• Works by acting like a purine or pyrimidine analog and incorporating itself into the DNA sequence causing faulty base pairing

• Works by competitive inhibition to prevent AMP production.