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Transplant Rejection

*Rejectio transplantati*

For medical students2 min readUpdated 2026-10-10

Transplant rejection is a pathological process in which the host organism recognizes transplanted tissue as foreign. This reaction is driven by an immune response against donor major histocompatibility complex (MHC) antigens, involving both cell-mediated immunity mechanisms and circulating antibodies.

Main TargetDonor major histocompatibility complex (MHC) antigens.

Key CellsDonor dendritic cells, which act as the most potent immunogens.

Hyperacute RejectionDevelops immediately due to preformed circulating antibodies in the blood.

HistologyVascular damage in the graft presents as classic vasculitis.

T-Cell Mechanisms (Cell-Mediated Immunity)

The initiation of rejection starts when recipient lymphocytes contact donor major histocompatibility complex (MHC) antigens. Notably, donor-derived dendritic cells residing within the transplanted organs are considered the most potent immunogens.

The pathway of T-cell response activation follows a strict sequence:

Primary contact: Host T cells recognize foreign dendritic cells directly within the graft tissue.
Migration: Upon recognition, cells migrate to regional lymph nodes.
Differentiation: Precursors of CD8+ lymphocytes (bearing specific receptors for MHC class I antigens) transform into mature cytotoxic T lymphocytes (CTLs).

The effector phase of cellular rejection is executed through two pathways. On one hand, mature CD8+ CTLs exert a direct effect by directly lysing (destroying) the graft tissue. On the other hand, CD4+ lymphocytes play a critical role. Their action mirrors delayed-type hypersensitivity (DTH) mechanisms. They actively secrete cytokines, leading to increased vascular permeability and a massive accumulation of macrophages and lymphocytes within the transplanted organ.

Humoral Mechanisms: Hyperacute Rejection

The humoral response is mediated by circulating antibodies and can manifest in two ways. The first and most aggressive of these is hyperacute rejection.

The primary prerequisite for its development is the presence of preformed antibodies against donor tissues in the recipient's blood before transplantation. High-risk groups include:

Recipients with a history of graft rejection.
Patients with a history of blood transfusions from MHC-mismatched donors (since transfused platelets and leukocytes carry MHC antigens, inevitably causing sensitization).

The dynamics of the process are rapid: rejection develops immediately after transplantation. The pathogenesis is driven by circulating antibodies forming immune complexes that deposit in the endothelium of the graft's blood vessels. Complement fixation occurs, triggering severe damage—an Arthus reaction.

Humoral Mechanisms in Non-Sensitized Recipients

The second variant of the humoral response occurs in the complete absence of prior host sensitization.

In this scenario, antibody production begins only after transplantation as a reaction to exposure to donor MHC class I and II antigens. Mechanisms of tissue damage include:

Complement-dependent cytotoxicity.
Antibody-dependent cellular cytotoxicity.
Deposition of newly formed antigen-antibody immune complexes.

The main target for attacking antibodies becomes the graft's blood vessels. Examining this process at the histological level using a transplanted kidney as an example, the morphological picture will fully correspond to classic vasculitis.

Mnemonic

To avoid confusing the targets of different mechanisms, use the rule: Cells hit cells, antibodies hit vessels. T-cell immunity (CD8+) directly lyses graft tissue, whereas humoral immunity (antibodies) forms complexes that deposit in the endothelium and cause vasculitis.

Frequently asked questions

What clinical and morphological types of transplant rejection are distinguished based on the time of onset?

Based on the provided sources, the following variants of transplant rejection are described:

Hyperacute rejection — develops immediately after organ transplantation when preformed antibodies against the donor are present in the recipient's blood.
Early rejection — in early stages, accompanied by thickening of the cortical layer with signs of surrounding edema; with progression, thinning of the cortical layer may occur, transitioning into atrophy in late stages.
Accelerated rejection reaction (second-set reaction) — occurs upon re-transplantation of tissues bearing the same antigens as the first graft; characterized by a shortened induction phase and rapid vascular thrombosis.

What is the difference between direct and indirect pathways of alloantigen recognition?

The difference lies in the source of antigen-presenting cells (APCs) and the form of the recognized major histocompatibility complex (MHC) molecule.

Characteristic	Direct Recognition	Indirect Recognition
APCs	Donor dendritic cells ("passenger leukocytes")	Recipient's own APCs
Recognition Target	Intact donor MHC molecule	Peptide fragments of donor MHC
Presentation Molecule	Donor MHC	Recipient's own MHC molecules
Activated Cells	Primarily CD8+ T cells	Usually CD4+ T lymphocytes

Specifically which cytokines do CD4+ lymphocytes secrete to cause delayed-type hypersensitivity during rejection?

During transplant rejection, activated CD4+ T lymphocytes secrete cytokines, specifically naming interferon-gamma (IFNγ).

The release of these substances leads to the following effects:

Activation of macrophages, which produce inflammatory factors.
Increased vascular permeability.
Accumulation of macrophages and lymphocytes in the tissue.
Development of local inflammation, microcirculatory disturbances, and thrombus formation.

As a result, the trophic supply of the transplanted organ is impaired, contributing to its destruction.

What is the primary cause of transplanted organ rejection?

The primary cause is the host immune system recognizing the transplanted tissue as foreign. The main antigens that trigger this response are the donor's major histocompatibility complex (MHC) antigens.

Why can previous blood transfusions cause organ rejection?

Leukocytes and platelets in donor blood carry MHC antigens. If the blood is not MHC-matched, the patient undergoes sensitization and develops preformed antibodies, leading to hyperacute rejection.

How exactly do CD4+ lymphocytes damage the graft?

They act via a delayed-type hypersensitivity mechanism. CD4+ cells secrete cytokines that increase vascular permeability and recruit macrophages and lymphocytes into the tissue to destroy the foreign material.

What histological picture is seen in humoral kidney rejection?

Since the main targets of circulating antibodies are the graft's blood vessels, microscopic examination reveals a picture of pronounced vasculitis.

Go deeper

The role of donor dendritic cells as potent immunogens.
Stages of CD8+ lymphocyte differentiation into cytotoxic cells.
Pathogenesis of the Arthus reaction in hyperacute rejection.
Mechanisms of complement-dependent cytotoxicity and cellular cytotoxicity.
Morphological signs of vasculitis in graft vessels.