104 Organ Donation, Types of Transplants, and Transplant Rejection

Importance of Matching in Transplantation:
Three key tests are conducted to ensure a close match and reduce the chances of organ transplant rejection:

1. Blood Type Matching: Ensures compatibility of ABO blood group and Rh(+/-) factor on Red Blood Cells (RBCs).  This is mandatory for a successful transplantation to occur.  See Table for details.
2. MHC Matching: DNA sequencing helps in matching Major Histocompatibility Complex (MHC, also known as Human Leukocyte Antigen, HLA) alleles for compatibility and increases the likelihood of organ acceptance.
3. Crossmatch Test: Involves test tube mixing of the recipient’s blood with the potential donor’s blood to check for circulating antibodies in the blood plasma that could reject the donor’s organs.

Blood and DNA matching before transplantation is crucial.  Biological family members are often closer matches than the general population due to shared inheritance of MHC alleles and blood types.  However, unless an individual has an identical twin, it is very difficult to find an exact match for all of the MHC genes.  Due to the lack of available organs and polymorphism of MHC genes, most often close matches rather than exact matches of MHC alleles between donors and recipients are used for donation.  Therefore, lifelong use of immunosuppressants by the recipient is typically required to ensure that organ is not targeted for destruction by the recipient’s immune system.

Blood Donation:

Blood Type Match:  As a quick reminder, Type O- is considered the universal donor and packed red blood cells (RBCs) from this donor can be given to any human successfully.  Type O- RBCs do not express antigen A, antigen B, or the Rh antigen or their cell surfaces, meaning that these Type O- RBCs will not be targeted for destruction by any anti-A, anti-B, or anti-Rh antibodies that are present in a recipient’s immune system.

Type AB+ is considered the universal recipient and can receive any type of human RBCs successfully.

Plasma donation is different than packed RBC donation.  Plasma contains antibodies, and therefore, for plasma donation, Type AB+ blood is considered the universal donor, as Type AB+ plasma will not contain antibodies against antigen A, antigen B, or the Rh antigen.

This all being said, the crossmatch test is still mandatory, as there are minor antigens present on RBCs that can invoke rejection, and therefore may make donor and recipient’s blood not compatible.

Types of Transplants: 

1. Allograft: Tissue is transferred between members of the same species, but is genetically different, such as from one human to another. An example is a mother donating to her daughter.  The term allogeneic is used if individuals are not genetically identical.  In this type of organ transplantation, the MHC genes are similar but may not be exactly identical.
2. Isograft: Tissue transferred between genetically identical individuals, such as identical twins, who share identical MHC sets and blood types.
3. Autograft: Tissue transferred within the same individual, such as a skin graft for burns or bone grafts for fractures.
4. Xenograft: Tissue transferred from one species to another, such as pig valves used in human heart surgeries.

Living tissue is preferable over cadaveric tissue due to less damage. Commonly transplanted organs in Canada include skin, cornea, bone, bone marrow, kidneys, liver, lungs, heart, pancreas, and intestinal tissues. There is an increased risk of rejection in patients with pre-existing antibodies from prior blood transfusions.

Transplant Rejection Mechanisms:
Transplant rejection often occurs due to a T cell-mediated hypersensitivity reaction, with inflammation, tissue necrosis, and rejection as common outcomes. There are two primary pathways of rejection, the direct and indirect pathways.

1. Direct Pathway: Involves the recipient’s CD8 cytotoxic T cells recognizing Class I MHC antigens present on the donated tissue.
2. Indirect Pathway: Involves the recipient’s CD4 helper T cells activating B cells and cytotoxic T cells via Class II MHC.
3. Immediate: A third pathway can occur in a recipient that has been previously exposed to antigens present on the donated tissue.  In this case the recipient’s plasma contains circulating antibodies that quickly bind to the non-self antigens on the donated tissue initiating the complement system and innate immune response.

Risk Factors for Transplant Rejection:

As mentioned, transplant success rates are higher with living donors, as well as ensuring blood and MHC matches. Some tissues, like heart valves, corneas, cartilage, and umbilical stem cells, do not require MHC matching due to low vascularity.  Corneal and cartilage allografts, for example, are more successful due to the lack of vascularization.  These tissues effectively are more “hidden” from the recipient’s circulating immune cells and antibodies.

Newborns can accept organs without MHC matching due to their immature immune systems.

However, most recipients require lifelong immunosuppressive drug treatment post-transplant and despite this, most donations needing replacement after 5-10 years due to chronic rejection.

Types of Rejection Based on Timeframe:

• Hyperacute: Immediate rejection due to the donor having pre-existing antibodies to the donor organ or graft’s MHC antigens.  A Type 3 hypersensitivity reaction occurs in which pre-existing antibodies attack and cause degeneration of the graft tissue’s blood vessels, resulting in lack of blood flow to the graft leads to ischemic necrosis of the graft tissue).  In this situation, antibodies, followed quickly by antibody activation of the complement system target the blood vessel walls of donated tissue for destruction.  Specifically, the antibodies attack antigens on blood vessel wall endothelial cells resulting in a rapid immune response that involves the complement system, and blood clotting that blocks blood vessels in the graft causing ischemia, hemorrhaging, and eventual necrosis of the graft.
•  Acute: Rejection within weeks due to T cell-mediated response (specifically a Type 4 hypersensitivity reaction in which memory T cells are stimulated by the donated tissues antigens and launch destructive adaptive immune response of the donated graft’s vasculature and tissue).  Acute rejection develops over several weeks as memory T cells take some time to proliferate and produce enough CD8+ Cytotoxic T cells (TC cells) that recognize Class I MHC on the transplant as non-self and destroy enough of the tissue to show signs and symptoms.  The activation of TC Memory cells is termed a direct pathway.  An indirect pathway of rejection can also occur, and this involves the activation of CD4+ Helper T memory cells, which are triggered by non-self Class II MHC complexes on the graft.  Once activated, the Helper T memory cells proliferate and Helper T cells (TH cells) launch both T cell-mediated immune responses and B cell humoral immune responses that target the donated graft tissue for destruction.
• Chronic: Rejection over months to years due to ongoing T cell-mediated damage.  Characterized as a Type 4 hypersensitivity Reaction involving CD8+ T cells targeting non-self MHC on transplanted tissue for destruction, leading to a gradual decline of graft function which can by asymptomatic for some time.  The tissue becomes infiltrated with macrophages and the ensuing damage leads to loss of functional tissue, and accumulation of more and more scarring).   It is rare to get a complete match of MHC molecules between the donor and recipient (in addition to matching blood types), as this is usually only possible with identical twins.   If there is a MHC molecular match between donor and recipient, chronic rejection can still occur, due to polymorphic antigens at minor histocompatibility antigens, termed minor H antigens.  It is most often CD8+ T cells that respond to minor H antigens.  Minor H antigens are self-peptides bound to MHC I on the graft cells that can become targets for the host’s immune system.  This can happen even when the MHC I peptides themselves are identically matched, because the self-peptides the MHC I display are from other cellular proteins which may not be a match to the donor, unless the individual is an identical twin donor.  For example, a female (XX) recipient that has been grafted with tissue from a donor male (XY), can lead to an immune response against minor H antigens that come from proteins expressed from the Y chromosome.  The opposite problem is less likely to occur, as male recipients’ immune systems could recognize most X chromosome proteins as potentially being self-proteins (unless differing polymorphisms are present, which is certainly a possibility).

Transplant Waitlists:
As of 2023, approximately 3,500 transplants occur annually in Canada, with nearly 3,000 being solid organ transplants. Transplant needs are categorized by province and tissue type. In 2022, 48,375 Canadians were living with end-stage kidney disease, with 29,809 relying on dialysis. About 3,800 people are on the transplant waitlist annually in Canada, with 73% waiting for a kidney, 13% for a liver, 6% for a lung, and 3% for a pancreas. Less than half of those on the waitlist receive a transplant each year, with 662 individuals either withdrawing or dying while waiting.

Registering to be an organ donor can save lives and support families.  Heart surgery, leukemia treatment, and severe injuries like car crashes often require multiple blood donors. Visit Canadian Blood Services to set up an appointment and donate blood in Canada, or Canada Health Services to register for organ donation. In BC, visit Transplant BC for more information.

Summary:

• Importance of Matching in Transplantation:
  • Three tests are done to ensure a match – and reduce the chances of organ transplant rejection:
    • 1. Blood Type must match (e.g., ABO blood group and Rh+/-)
    • 2. MHC matching increases the chance of organ acceptance.
    • 3. Cross match test – involves mixing the blood of the recipient with that of the potential donor to determine whether the recipient has any circulating antibodies present that will reject the donor’s blood or organs.
  • Blood and DNA matching before transplantation is crucial.
  • DNA Sequencing for Matching MHC/HLA alleles helps to determinee compatibility.
  • Biological family members are often better matches due to shared inheritence of MHC and blood types.
• Types of Transplants:
  • Allograft: Tissue transferred between members of the same species but may differ genetically; e.g., one human to another human (allogenic if MHC groups are similar – living tissue is preferable, not as damaged)
    • E.g., Mother to daughter.
  • Isograft: Tissue between genetically identical individuals.
    • E.g., Identical twins (identical MHC/HLA set and ABO group and Rh+/-)
  • Autograft: Tissue transferred from one part of the body to another part of the same individual
    • E.g., Skin graft for burns.  Bone grafts in the case of comminuted bone fractures
  • Xenograft: Tissue transferred from a member of one species to a different species.
    • E.g., Pig valves to human heart.
• Memory Tricks:
  • The prefix auto is derived from the Greek word for self.
  • The prefix allo is derived from the Greek word allos for other.
  • The prefix iso is derived from the Greek word isos for ‘equal to’ or ‘the same’.
  • The prefix xeno is derived from the Greek word xeno for foreigner or stranger
  • Autopilot refers to self driving (Autograft= graft from self).
  • Ally refers to friend (Allograft=graft from friend).
  • Iso…could remember as Is = plural of I, or I squared.
  • Xeno… could remember as externally sourced.
• Preferred Tissue Source:
  • Living tissue is preferable over cadaveric tissue due to less damage.
• Commonly Transplanted Organs in Canada:
  • Skin, cornea, bone, bone marrow, kidneys, liver, lungs, heart, pancreas, intestinal tissues.
  • Increased risk of rejection in patients who have pre-existing antibodies from prior blood transfusions
• Transplant Rejection:
  • Cause: Usually a T cell-mediated hypersensitivity reaction (Type 4).
  • Involvement: Sometimes B cells are involved (humoral response).
  • Outcome: Inflammation, tissue necrosis, and rejection.
• Pathways of Rejection:
  • Direct Pathway: Involves CD8 cytotoxic T cells recognizing Class 1 MHC antigens.
  • Indirect Pathway: Involves CD4 helper T cells activating B cells and cytotoxic T cells via Class 2 MHC.
• Success Factors for Donations:
  • Greatest success with living donors and MHC matches.
  • Heart valves, cornea, cartilage and umbilical stem cells do not require MHC matches due to low vasculature.
  • Corneas and cartilage allograft transplants have a good chance of success due to lack of vascularization of these tissues.
  • Newborns can accept organs without MHC matching due to immature immune systems.
• Post-Transplant Medication:
  • Recipients often require lifelong immunosuppressive drugs.
  • Most donations need replacing after 5-10 years due to chronic rejection
• Types of Rejection Based on Timeframe:
  • Hyperacute: Immediate rejection due to the donor having pre-existing antibodies to the donor organ or graft’s MHC antigens.  This is a Type 3 Hypersensitivity Reaction.
  • Acute: Rejection within weeks due to T cell-mediated response (specifically a Type 4 hypersensitivity reaction in which memory T cells are stimulated by the donated tissues antigens and launch destructive adaptive immune response of the donated graft’s vasculature and tissue).  Acute rejection develops over several weeks as memory T cells take some time to proliferate and produce enough CD8+ Cytotoxic T cells (T_C cells) that recognize Class I MHC on the transplant as non-self and destroy enough of the tissue to show signs and symptoms.  The activation of T_C Memory cells is termed a direct pathway.  An indirect pathway of rejection can also occur, and this involves the activation of CD4+ Helper T memory cells, which are triggered by non-self Class II MHC complexes on the graft .  Once activated, the Helper T memory cells proliferate and Helper T cells (T_H cells) launch both T cell-mediated immune responses and B cell humoral immune responses that target the donated graft tissue for destruction.
  • Chronic: Rejection over months to years due to ongoing T cell-mediated damage.  Characterized as a Type 4 hypersensitivity Reaction involving CD8+ T cells targeting non-self MHC on transplanted tissue for destruction, leading to a gradual decline of graft function which can by asymptomatic for some time.  The tissue becomes infiltrated with macrophages and the ensuing damage leads to loss of functional tissue, and accumulation of more and more scarring).   It is rare to get a complete match of MHC molecules between the donor and recipient (in addition to matching blood types), as this is usually only possible with identical twins.   If there is a MHC molecular match between donor and recipient, chronic rejection can still occur, due to polymorphic antigens at minor histocompatibility antigens, termed minor H antigens.  It is most often CD8+ T cells that respond to minor H antigens.  Minor H antigens are self-peptides bound to MHC I on the graft cells that can become targets for the host’s immune system.  This can happen even when the MHC I peptides themselves are identically matched, because the self-peptides the MHC I display are from other cellular proteins which may not be a match to the donor, unless the individual is an identical twin donor.  For example, a female (XX) recipient that has been grafted with tissue from a donor male (XY), can lead to an immune respones against minor H antigens that come from proteins expressed from the Y chromosome.  The opposite problem is less likely to occur, as male recipient’s immune system could recognize most X chromosome proteins as potentially being self-proteins (unless differing polymorphisms are present, which is certainly a possibility).
• Transplant Waitlists
  • As of 2023, approximately 3,500 transplants occur per year in Canada, with almost 3,000 involving solid organ transplants.
  • Transplants are categorized by province and tissue type.
  • In 2022, there were 48, 375 Canadians living with end-stage kidney disease, with 29,809 of these inidividuals relying on dialysis
  • As of 2022, approximately 3,800 people are on the transplant waitlist in Canada annually (73% waiting for a kidney, 13% waiting for a liver, 6% waiting for a lung, 3% waiting for a pancreas).
  • Less than half of those on the waitlist receive a transplant each year.
  • 662 people either withdrew or died while waiting for a transplant.
  • Signing an organ donor card can help save lives and support families.
  • The author has signed their organ donor card.
  • Heart surgery requires 5 blood donors
  • Leukemia treatment requires 8 blood donors per week
  • Car crash victims can require up to 50 blood donors
  • Visit Canadian Blood Services to find out how easy it is set up an appointment and donate blood in Canada
  • Visit Canada Health Services to register for organ donation.
  • In BC, visit Transplant BC for more information.