Transplantation And Compatibility Concepts

The HLA / MHC System

The human leukocyte antigen (HLA) system is the human major histocompatibility complex (MHC), encoded on the short arm of chromosome 6. It is the most polymorphic system in humans and the primary determinant of transplant compatibility. HLA genes are inherited as a haplotype (a linked set from each parent) in a codominant fashion, so each person expresses both maternal and paternal antigens.

Because siblings inherit one haplotype from each parent, two siblings have a 25% chance of being HLA-identical, a 50% chance of sharing one haplotype, and a 25% chance of sharing none. This is why related donors are sought for stem-cell transplants. HLA-DR matching is especially important for kidney graft survival.

Compatibility Testing

Three laboratory steps establish compatibility:

1. HLA typing of donor and recipient (now usually molecular/DNA-based, formerly serologic microcytotoxicity).
2. Antibody screening (PRA, panel-reactive antibody): measures the percentage of a panel to which the recipient has preformed HLA antibodies — a high PRA means a highly sensitized, hard-to-match recipient.
3. Crossmatch: recipient serum is tested against donor lymphocytes. A positive crossmatch (recipient antibody binds donor cells) is a contraindication to transplant because it predicts hyperacute rejection.

Sensitization to HLA antigens arises from prior pregnancy, transfusion, or transplantation.

Types Of Graft Rejection

The exam expects you to match each rejection type to its mechanism and timing.

A positive crossmatch predicts hyperacute rejection, which is why crossmatching is mandatory. Acute rejection is the target of most immunosuppressive therapy (e.g., calcineurin inhibitors such as cyclosporine and tacrolimus).

Graft-Versus-Host Disease (GVHD)

GVHD is the mirror image of rejection: instead of the host rejecting the graft, immunocompetent donor T cells attack an immunocompromised recipient's tissues (skin, gut, liver). It classically follows allogeneic bone marrow / hematopoietic stem-cell transplantation and can also follow transfusion of non-irradiated cellular blood products into an immunocompromised patient.

Prevention in transfusion: gamma or X-ray irradiation of cellular blood components inactivates donor lymphocytes, preventing transfusion-associated GVHD. This is required for at-risk recipients (severe immunodeficiency, intrauterine and neonatal transfusions, hematopoietic transplant recipients, and directed donations from blood relatives).

ABO And Transplant

For solid-organ transplants, ABO compatibility generally follows the same rules as transfusion, because A and B antigens act as histocompatibility antigens on graft endothelium; an ABO-incompatible organ can trigger hyperacute rejection just as preformed HLA antibodies do.

High-Yield Traps

• Class I (A, B, C) is on all nucleated cells and presents to CD8 cells; class II (DR, DQ, DP) is on antigen-presenting cells and presents to CD4 cells — do not reverse them.
• A positive crossmatch contraindicates transplant (predicts hyperacute rejection).
• Hyperacute = preformed antibody/minutes; acute = T cells/weeks — timing is the discriminator.
• Irradiation, not leukoreduction, prevents transfusion-associated GVHD by inactivating donor lymphocytes.

HLA And Disease Association

Beyond transplantation, certain HLA alleles are statistically associated with autoimmune and other diseases, a relationship the exam may test. The strength of the link is expressed as a relative risk. Classic associations include HLA-B27 with ankylosing spondylitis and reactive arthritis, HLA-DR3/DR4 with type 1 diabetes, HLA-DR2 with multiple sclerosis and Goodpasture syndrome, and HLA-B*57:01 with abacavir hypersensitivity (now screened before prescribing the drug).

These are associations, not diagnostic tests — a patient can carry the allele without the disease — so the link guides risk assessment rather than confirming a diagnosis.

Platelet And Transfusion Immunology

HLA antigens also drive two transfusion problems. Platelet refractoriness occurs when a recipient develops HLA antibodies (from pregnancy, transfusion, or transplant) and fails to achieve the expected platelet count increment; the solution is HLA-matched or crossmatched platelets. Febrile non-hemolytic transfusion reactions are often caused by recipient antibodies against donor leukocyte (HLA) antigens or by accumulated cytokines, and are reduced by leukoreduction.

The Crossmatch Decision And Donor Selection

Matching a donor to a recipient combines several immunologic steps, and the exam frames them as a workflow:

Worked example: A highly transfused, multiparous renal candidate has a PRA of 95%. The high panel-reactive antibody means she is broadly sensitized and will react with most donors, so finding a negative crossmatch is difficult; transplanting across a positive crossmatch would precipitate hyperacute rejection. This integrates sensitization history, antibody screening, and crossmatch interpretation into a single decision — exactly the correlation reasoning the MLS exam rewards.

Additional Traps

• HLA-disease links are associations (relative risk), not diagnostic confirmation.
• Platelet refractoriness from HLA antibodies is solved by HLA-matched platelets, not more random units.
• A high PRA signals broad sensitization and predicts difficulty finding a compatible donor.