T-cell mechanisms (Cellular immunity)
The initiation process of rejection starts when recipient lymphocytes come into contact with the donor's major histocompatibility complex (MHC) antigens. Notably, dendritic cells located within the donor organs are considered the most potent immunogens in this process.
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: following recognition, the cells migrate to regional lymph nodes.
- Differentiation: CD8+ lymphocyte precursors (possessing specific receptors for class I MHC antigens) transform into mature cytotoxic T lymphocytes (CTLs).
The effector phase of cellular rejection is carried out via two pathways. On the 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 is analogous to delayed-type hypersensitivity (DTH) mechanisms. They actively secrete cytokines, leading to increased vascular permeability and a massive accumulation of macrophages and lymphocytes in the area of the transplanted organ.
Humoral mechanisms: Hyperacute rejection
The humoral response is mediated by circulating antibodies and can manifest in two variants. The first and most aggressive of these is hyperacute rejection.
The primary condition for its development is the presence of preformed antibodies against donor tissues in the recipient's blood prior to transplantation. The high-risk group includes:
- Recipients with a history of transplant rejection.
- Patients following blood transfusions from donors not matched for MHC (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 due to circulating antibodies forming immune complexes that deposit in the endothelium of the transplanted organ's vessels. Complement fixation occurs, triggering severe damage—a Arthus reaction develops.
Humoral mechanisms in unsensitized recipients
The second variant of the humoral response occurs provided there is a complete absence of prior host sensitization.
In this case, antibody production begins only after transplantation as a response to the exposure of donor class I and II MHC 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 the attacking antibodies becomes the graft 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.
Briefly: answers to topical questions
What clinical and morphological types of transplant rejection are distinguished depending on the time of their development?
The cited sources describe the following variants of transplant rejection:
- Hyperacute rejection — develops immediately after organ transplantation in the presence of preformed antibodies against the donor in the recipient's blood.
- Early rejection — in early stages, it is accompanied by thickening of the cortical layer with signs of surrounding edema; with progression, thinning of the cortical layer with progression to atrophy is possible in late stages.
- Accelerated rejection reaction (second-set reaction) occurs upon retransplantation of tissues bearing the same antigens as the first graft; it is characterized by a shortened inductive phase and rapid vascular thrombosis.
What is the difference between the 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 |
|---|---|---|
| APC | 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 | Predominantly CD8+ T cells | Typically CD4+ T lymphocytes |
Specifically, which cytokines do CD4+ lymphocytes secrete to cause delayed-type hypersensitivity during rejection?
During graft rejection, activated CD4+ T lymphocytes secrete cytokines, specifically including 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, impaired microcirculation, and thrombus formation.
As a result, the trophism of the transplanted organ is impaired, contributing to its destruction.
To avoid confusing the targets of different mechanisms, use the rule: Cells attack cells, antibodies attack vessels. T-cell immunity (CD8+) directly lyses graft tissue, whereas humoral immunity (antibodies) forms complexes that deposit in the endothelium and cause vasculitis.
Class and exam questions
What is the main cause of transplanted organ rejection?
The main cause is the host immune system recognizing the transplanted tissue as foreign. The primary antigens triggering the organism's response are the donor major histocompatibility complex (MHC) antigens.
Why can a prior blood transfusion become a cause of organ rejection?
Leukocytes and platelets in donor blood carry MHC antigens. If the blood was not matched by MHC, the patient becomes sensitized and preformed antibodies are generated, 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 tissue.
What histological picture can be seen in humoral renal rejection?
Since circulating antibodies primarily target the graft's blood vessels, microscopy will reveal a picture of marked vasculitis.
What else to study on this topic
- 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 cytolysis.
- Morphological signs of vasculitis in graft vessels.
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