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Immunology Lecture 32: Transplantation Immunology
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Immunology Lecture 32: Transplantation Immunology

Introduction to Transplantation Immunology

Overview: This section provides an overview of transplantation immunology, including the types of organs that are typically transplanted and the process of transplantation. It also explains the hallmarks of the adaptive immune response in transplant rejection.

Types of Transplants

  • Heart, kidney, pancreas, intestine, liver, and lung are all commonly transplanted organs.
  • Other types of transplants include cornea, skin grafts, blood transfusions, and bone marrow transplants.

Process of Transplantation

  • When an organ becomes available for transplant, it is tested for matches and quick action must be taken to keep the organ alive and viable.
  • The patient has likely been waiting for a long time and is excited to receive the call.
  • A delicate operation is performed to transplant the organ.

Adaptive Immune Response in Transplant Rejection

  • Unfortunately, sometimes an immune response can cause the organ to be rejected.
  • Transplant rejection displays hallmarks of the adaptive immune response, including primary and secondary responses.
  • T-cells are involved in graft rejection and can be isolated from the spleen of a mouse who has experienced first set rejection.
  • When these t-cells are transplanted into a naive mouse, second set rejection occurs.
  • The textbook also provides an illustration of what happens when a graft is accepted, including revascularization and healing.
  • With first set rejection, cells infiltrate the grafted skin at 7-10 days, eventually killing it.
  • Second set rejection occurs much quicker.

Hyperacute Rejection

Overview: Hyperacute rejection is a type of transplant rejection that occurs very quickly due to pre-existing antibodies. It is characterized by the binding of antibodies to endothelial cells in the graft, occlusion of the kidney, inflammation, and eventual rejection of the graft.

Types of Transplantation

  • Auto graft: A transplant from oneself or someone who is genetically identical. Examples include skin grafting and donating blood.
  • Allograft: A transplant between two members of the same species who are not genetically identical.
  • Xenograft: A transplant from a different species.

Types of Rejection

  • Hyperacute Rejection: Occurs very quickly due to pre-existing antibodies. Characterized by the binding of antibodies to endothelial cells in the graft, occlusion of the kidney, inflammation, and eventual rejection of the graft.
  • Acute Rejection: Looks similar to a type 4 hypersensitivity response.
  • Chronic Rejection: Looks similar to a type 3 hypersensitivity response.

Prevention

  • Hyperacute rejection is typically caused by one specific antigen, making it easier to check for and protect against.

Major and Minor Antigens in Transplant Rejection

Overview: This section discusses the major and minor antigens that can lead to transplant rejection, as well as the importance of blood typing before a transplant. It also covers the two phases of acute rejection and the role of the major histocompatibility complex (MHC).

Major and Minor Antigens

  • Everyone has anti-B antibodies, but if A and B are self-antigens, then no antibodies are produced.
  • Blood typing is done to combat hyperacute rejection, which is the most common antigen that causes it.
  • Acute rejection is T-cell mediated and involves two phases: sensitization and rejection.

The Role of the Major Histocompatibility Complex (MHC)

  • The MHC is the most frequent antigen that causes transplant rejection.
  • The MHC is responsible for activating T cells in a secondary lymphoid organ, which then travel back to the graft and destroy it.
  • The MHC is the predominant antigen that leads to T cell activation and subsequent rejection.

MHC and Transplant Matching

Overview: This section discusses the importance of MHC in transplant matching, as well as how the T-cell receptor recognizes MHC plus peptide.

MHC and Transplant Rejection

  • Genetically identical mice can have different MHC, leading to graft rejection.
  • MHC is an important antigen in transplant matching.
  • The number of MHC mismatches is related to the percentage of transplants that survive 10 years.

T-Cell Receptor Recognition

  • T-cell receptors bind to a surface containing both MHC and peptide.
  • T-cells cannot distinguish between MHC and peptide amino acids.
  • Mismatched MHC leads to acute rejection.
  • T-cells recognize a surface of amino acids, not individual amino acids.
  • Some MHCs may look similar but present different peptides.
  • Zinkernagel and Doherty were lucky in their experiment.
  • Matching as many MHCs as possible is the goal.

Direct and Indirect Auto Recognition

Overview: This section explains the two ways that an MHC can be an antigen: direct auto recognition and indirect auto recognition.

Direct Auto Recognition

  • In direct auto recognition, the recipient's T-cells are able to bind directly to the MHC from the donor, activating the T-cell and causing it to kill the kidney.
  • This is largely what is seen in the mice who were getting transplants of foreign skin with foreign MHC.

Indirect Auto Recognition

  • In indirect auto recognition, some cell of the donor dies and is phagocytosed by an antigen-presenting cell from the recipient.
  • The MHC protein from the donor is degraded and presented on the recipient's MHC.
  • This activates the recipient's T-cells, which can then go and kill the kidney.

DQ1 and DQ2

  • DQ1 and DQ2 are structurally and genetically the same, but they are not the same.
  • When transplanting a kidney, it is important that the kidney presents the same kind of MHC that the thymus does, so that if there is a virus, the T-cells can recognize it and get rid of it.
  • Otherwise, the T-cells will not be activated unless there is a foreign peptide.

MHC Matching and Transplant Rejection

Overview: This section covers the basics of MHC matching and transplant rejection, including acute, chronic, and minor histocompatibility antigens.

MHC Matching

  • Mice are inbred, so it is relatively easy to find a perfect MHC match for a kidney transplant.
  • Humans, however, are outbred, making it almost impossible to find a perfect MHC match.
  • Even if a perfect MHC match is found, the transplant is likely to only last 13 years, with a 33% chance of lasting 10 years.

Transplant Rejection

  • Acute rejection is the most common type of rejection and is caused by mismatches in MHC molecules.
  • Minor histocompatibility antigens are any gene that varies from one person to another, leading to foreign proteins.
  • Chronic rejection is less well understood and takes the longest to occur. It is believed to be antibody-mediated.

Solid Organ Transplantation

Overview: This section covers the differences between chronic and hyperacute rejection in solid organ transplantation, as well as the reasons why bone marrow transplants are used.

Chronic vs Hyperacute Rejection

  • Chronic rejection involves priming and activating B-cells to produce antibodies, while hyperacute rejection involves pre-existing antibodies.
  • In chronic rejection, the mismatch between donor and recipient MHC leads to B-cell recognition and antibody production.

Reasons for Bone Marrow Transplants

  • Bone marrow transplants are used to treat immunodeficiencies, cancers, and other diseases.
  • Bone marrow is taken from the hip bone and contains hematopoietic stem cells, memory B cells, and memory T cells.
  • Radiation or chemotherapy is used to kill rapidly dividing cells, including those of the immune system.

Graft-versus-Host Disease

  • GVHD occurs when memory T cells from the donor attack the recipient's lymph nodes.
  • GVHD is the opposite of host-versus-graft disease, where the graft (e.g. kidney) tries to kill the host.

Liver Degradation

Overview: This section discusses the process of liver degradation and how it can be prevented or treated. It also covers the importance of MHC matching in bone marrow transplantation, as well as the use of cytotoxic drugs and ctla4 IG to prevent rejection.

Preventing Liver Degradation

  • Bone marrow transplants are no longer used, as stem cell transplants are now preferred due to their reduced risk of graft-versus-host disease.
  • Stem cells can also be found circulating in the blood, making bone marrow transplantation much easier.

MHC Matching

  • MHC matching is still important in bone marrow transplantation, but the importance is different. If there is no MHC matching, T cells will not be able to recognize the recipient's cells, leading to a lack of adaptive immune response.
  • Some mismatches or matches are sufficient, and in some cases, sinus is used to ameliorate this issue.

Cytotoxic Drugs and ctla4 IG

  • Cytotoxic drugs are used to kill rapidly dividing cells, and cyclosporine was introduced in 1983, increasing the success rate of heart transplants.
  • ctla4 IG binds to b7, preventing T cells from becoming energized and rejecting the graft. This molecule has also been used for autoimmunity and cancer therapy.

Organ Donation Systems

Overview: This section discusses the differences between opt-in and opt-out organ donation systems, as well as the potential for using miniature swine as organ donors.

Opt-In vs Opt-Out Systems

  • In the United States, an opt-in system is used for organ donation, meaning that individuals must actively check a box to become an organ donor.
  • In other countries, an opt-out system is used, meaning that individuals are assumed to be organ donors unless they explicitly state otherwise.
  • Studies have shown that opt-out systems result in higher rates of organ donation than opt-in systems.

Miniature Swine as Organ Donors

  • Miniature swine have organs that are the same size as human organs, making them potential organ donors.
  • Scientists are genetically engineering pigs to make their organs compatible for human transplantation.
  • Other solutions being explored include generating tissues from stem cells and developing mechanical devices.
  • Immunologists are also studying ways to address the issue of T cells attacking transplanted organs.