Organ Rejection

HLA

Human leukocyte antigen complex = the human MHC; helps the immune system recognize self from non-self

Why is HLA matching important in transplant?

HLA determines compatibility; a mismatch lets the recipient's immune system recognize the graft as foreign, leading to rejection

MHC class I (HLA-A, B, C)

Found on almost all nucleated cells; mismatch is recognized by CD8 T cells

MHC class II (HLA-DP, DQ, DR)

Found on B cells, APCs, and activated T cells; mismatch is recognized by CD4 T cells

HLA testing vs blood typing

HLA testing is more complicated: there are many more HLA markers than blood types

Purpose of HLA testing

Assess compatibility of recipients and potential donors before transplant

Causes of HLA antibody production

Blood or platelet transfusions, prior transplant, pregnancy

Why do these cause HLA antibodies?

Each exposes the person to someone else's HLA, so they form antibodies against it, making future matching harder

Best possible donor

The donor whose HLA best matches the recipient (lower risk of complications)

HLA typing example: perfect match

10/10 match: all HLA antigens match

HLA typing example: half match

5/10 match: only half of the antigens match

Panel of reactive antibodies (PRA)

Estimate of the percentage of the donor population a recipient might be incompatible with due to preformed HLA antibodies

Higher PRA means

Greater risk of immune injury (the patient is more sensitized)

ABO matching timing

Must be done PRIOR to grafting

Where are ABO antigens found?

On RBCs AND on the epithelial and endothelial cells lining blood vessels

Outcome of ABO (blood type) mismatch

Hyperacute rejection

Blood type mismatch: hypersensitivity type

Type II hypersensitivity (antibody-mediated)

Universal donor (packed RBCs)

Type O

Universal recipient (packed RBCs)

Type AB

Type O blood: antigens and antibodies

No antigens on RBCs; anti-A and anti-B antibodies

Type A blood: antigens and antibodies

A antigen; anti-B antibodies

Type B blood: antigens and antibodies

B antigen; anti-A antibodies

Type AB blood: antigens and antibodies

A and B antigens; no antibodies

Type A recipient can receive from

A or O donors

Type B recipient can receive from

B or O donors

Type AB recipient can receive from

A, B, AB, or O donors (all)

Type O recipient can receive from

O donors only

Type O donor can give to

A, B, AB, and O recipients (all)

Type AB donor can give to

AB recipients only

Type A recipient gets a type B organ

Incompatible: recipient's anti-B antibodies cause hyperacute rejection

Type O recipient gets a type A organ

Incompatible: recipient's anti-A antibodies cause hyperacute rejection

Type B recipient gets a type AB organ

Incompatible: recipient's anti-A antibodies cause hyperacute rejection

Type AB recipient gets a type O organ

Compatible: AB recipient has no anti-A or anti-B antibodies

Rh positive blood

Rh antigen on RBCs; no Rh antibodies

Rh negative blood

No Rh antigen on RBCs; may have Rh antibodies

Hyperacute rejection: cause

Recipient has PRE-FORMED antibodies from a blood type (ABO) mismatch

Hyperacute rejection: timing

Immediate

Hyperacute rejection: presentation

Clotting pathways activate, forming thrombi in capillaries and arterioles; occlusion leads to ischemia and necrosis of the graft

Hyperacute rejection: treatment

Irreversible; CANNOT be treated, so it MUST be prevented with blood typing

Acute rejection: cause

HLA (MHC class I and/or II) mismatch; T-cell mediated

Acute rejection: timing

Delayed (days to years); most often within 3 months, but can occur any time

Acute rejection: prevention

Perfect HLA match or immunosuppression therapy

Hyperacute vs acute rejection

Hyperacute: immediate, blood type mismatch, pre-formed antibodies, irreversible. Acute: delayed, HLA mismatch, T-cell mediated, preventable with HLA matching or immunosuppression

General presentation of rejection

Patient feels unwell and organ function declines (kidney: stops making urine); chronic rejection may be silent, so frequent labs are needed

HLA inheritance

Immediate family members inherit the same HLA markers, but a sibling can be a full match, half match, or no match

Direct allorecognition: whose APCs?

DONOR APCs migrate out of the graft to lymph nodes and present non-self MHC I and II to T cells

Direct allorecognition: strength and timing

Very vigorous (large number of T cells activated); occurs early after transplant

Indirect allorecognition: whose APCs?

RECIPIENT APCs enter the graft and present donor proteins on MHC II only (no direct MHC I activation)

Indirect allorecognition: strength and rejection type

Less vigorous or equivalent to direct; contributes to CHRONIC rejection