How T cells recognize foreign molecules
The initiation of the immune response depends on antigen-presenting cells (APCs), the primary ones being dendritic cells (Langerhans cells play this role in the skin). The recipient's T cells can recognize donor MHC molecules via two pathways:
- Indirect recognition. Donor MHC is endocytosed by recipient dendritic cells, degraded in endosomes, and loaded onto self MHC-II molecules. This process takes place in the regional lymph node and activates CD4+ T lymphocytes. The source of foreign antigen is the so-called "passenger cells"—donor dendritic cells migrating from the graft.
- Direct recognition. The T-cell receptor (TCR) directly binds to the intact donor MHC molecule on the surface of the donor APC. This mechanism predominates in the activation of CD8+ T cells.
Cell migration and tissue destruction mechanisms
The resulting effector cells (Th1 and cytotoxic lymphocytes) enter the bloodstream. Due to the expression of chemokine receptors (CCR1, CCR2, CCR3, CCR5), they home to the graft, where concurrent inflammation is invariably present. Macrophages and natural killer (NK) cells migrate there as well. Massive lymphoid infiltration becomes the main morphological hallmark of the reaction.
The rejection itself consists of two components:
- T-cell cytolysis (CD8+ component). NK cells (responding to the absence of "self" MHC) and cytotoxic T lymphocytes destroy graft cells via perforin- and Fas-dependent pathways. The cytokine IFNγ secreted by them stimulates apoptosis and maintains inflammation.
- Local inflammation and trophic impairment (CD4+ component). Th1 cells are stimulated by peptides presented within macrophage MHC-II. Via the CD40 molecule and cytokines (IFNγ, TNFα), they activate macrophages. These begin to secrete reactive oxygen species (ROS), nitric oxide (NO), and enzymes. This leads to local inflammation, microcirculatory thrombosis, and tissue death due to nutrient deprivation.
Accelerated rejection (second-set reaction)
If tissues with the same antigens are retransplanted into a recipient, a second-set reaction develops. It is characterized by a shortened inductive phase and the absence of full vascularization.
Due to the rapid activation of memory cells, effector T lymphocytes immediately begin producing cytokines, stimulating macrophages. If a vascularized organ is transplanted, a thrombus rapidly forms in the vessel. Blood supply is not established (a "white graft" appears), and ischemia coupled with local inflammation quickly leads to organ destruction.
Humoral antibodies and xenotransplantation
According to P. Medawar's rule, humoral antibodies do not play a key role in classical allograft rejection. Sometimes they even exert a protective effect (antigen blockade phenomenon), shielding the target cell from T lymphocytes. Direct competition between antibodies and T cells is rare since their epitopes usually do not overlap. However, antibodies can recruit macrophages and NK cells for cytolysis.
The situation changes radically in xenotransplantation (transplantation from animals). Humans initially possess natural antibodies against α-glycan residues present on animal cells. This triggers a rapid reaction with vasospasm, clinically resembling a secondary rejection (second set).
Bone marrow transplantation (BMT) and GVHD
BMT is used to compensate for hematopoietic failure (cytopenia) or after radiation-induced bone marrow destruction in the treatment of hemoblastosis. Unlike solid organ transplantation, bone marrow is administered as cell suspensions. NK cells and antibodies play a leading role in its rejection.
The main danger of BMT is graft-versus-host disease (GVHD). The transplanted material contains mature donor T lymphocytes that recognize recipient antigens as foreign and begin to destroy the host's tissues. Acute and chronic forms of GVHD are distinguished.
Briefly: answers to topical questions
What conditions (criteria) are necessary for the development of the graft-versus-host disease (GVHD) reaction?
The development of graft-versus-host disease (GVHD) requires the presence of immunocompetent cells in the graft and antigenic differences in the recipient. The main conditions are:
- Presence of T lymphocytes — the presence of mature donor T cells within the transplanted allogeneic bone marrow or transfused blood (leukocyte mass).
- Vector of aggression — the immune reaction is carried out by the transplanted cells and directed strictly against the recipient's (host's) antigens.
What are the types of allograft rejection according to the time of onset?
Based on the time of onset, three main types of allograft rejection are distinguished:
- Hyperacute rejection — develops within 1 to 5 days. The cause is the presence of pre-existing antibodies in the recipient (the result of past blood transfusions or pregnancies).
- Acute rejection — occurs within a period of 5 to 30 days. The mechanism is driven by the activation of cellular immunity.
- Chronic rejection — develops 6 months or more after surgery. Cellular immunity also predominates in the pathogenesis.
What are the mechanisms of chronic transplant rejection?
The mechanism of chronic transplant rejection is predominantly driven by cellular immunity reactions. The following components are involved in the process:
- Cytotoxic T lymphocytes (CD8+) — recognize foreign antigens and directly attack graft cells.
- Natural killer cells (NK cells) — participate in a direct attack on the transplanted tissues.
- Type 2 T helper cells (Th2) — stimulate the humoral response by activating B lymphocytes to synthesize antibodies.
In case of mismatches at minor histocompatibility loci, the reaction proceeds slowly, leading to the gradual death of graft cells and their replacement by host cells.
Which classes of immunosuppressants are used to prevent transplant rejection?
To prevent transplant rejection, sources confirm the use of immunosuppressants, including sirolimus and tacrolimus. Post-kidney transplant regimens also mention cyclosporine, prednisolone, and mycophenolate mofetil.
Direct recognition: the T cell "looks into the face" of an intact MHC molecule. Indirect recognition: "examines it in parts," when the recipient's own dendritic cell has digested foreign MHC and presents its peptides.
Class and exam questions
What are "passenger cells"?
These are allogeneic donor dendritic cells that migrate from the transplanted graft into the recipient's lymph nodes. They serve as the primary source of donor MHC molecules to trigger the immune response.
Do antibodies necessarily destroy the transplanted organ?
No, during primary allograft rejection, their role is minimal. In some cases, they even protect the organ by blocking antigens on the cell surface from T lymphocyte attack.
Why does the cytotoxic lymphocyte response not develop to its full extent during retransplantation (second-set)?
Due to rapid blood supply disruption and thrombosis (caused by memory cells and macrophages). The graft is in a state of severe ischemia, which inherently leads to its rapid destruction.
What else to study on this topic
- Mechanisms of Fas-dependent and perforin-mediated apoptosis
- The role of chemokine receptors (CCR1-CCR5) in lymphocyte migration
- FcR-dependent activation of macrophages by immune complexes
- Pathogenesis and differences between acute and chronic GVHD
- Antigenic structure of α-glycan residues
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