Graft rejection
DR/Sarah Samy
Lecturer of Microbiology&Immunology
Faculty of Medicine
Suez University
History of transplantation
• In 1908, the 1st report of kidney transplantation (KT)
in 9 cats; some of those receiving kidney from other
cats maintained urinary output for up to 25 days
• In 1935, a Russian surgeon attempted the 1st KT in
human, however it failed because of mismatched
blood type
• Today kidney, pancreas, heart, lung, liver, blood, bone
marrow, skin and cornea transplantation are
performed
Graft types
• There are different types depending on the source of the new
tissue or organ:
1-Allografts:tissues that are transplanted from one genetically
distinct individual to another within the same species .
2-Isograft: the transplant of tissue from a genetically identical twin
donor to the recipient.
3-Autograft : tissues are transplanted from one area on an individual
to another area on the same individual (e.g., a skin graft on a burn
patient), it is known as an Autograft .
4-xenograft: If tissues from an animal are transplanted into a human
Graft rejection
• Graft rejection occurs when the recipient’s immune system
attacks the donated graft and begins destroying the
transplanted tissue or organ. The immune response is
usually triggered by the presence of the donor’s own
unique set of HLA proteins, which the recipient’s immune
system will identify as foreign.
• The degree of similarity between the HLA genes of the
donor and recipient is known as histocompatibility; the
more genetically compatible the donor and the recipient,
the more tolerant the recipient’s immune system should
be of the graft.
Mechanism of graft rejection
• The process of graft rejection can be divided into
two stages (in the absence of pre-existing antibodies)
1.
Sensitization
stage
2. Effector
stage
During the sensitization phase
• CD4 and CD8 T cells recognize alloantigens expressed on cells of the
foreign graft and proliferate in response.
• This sensitization phase takes some time, which is why the effector
phase of acute rejection typically manifests 7 to 10 (or more) days
later, depending on the immune suppression regimen.
• The hallmark of the effector phase is a large influx of leukocytes,
especially CD4 T cells and macrophages.
• Host T helper cell becomes activated and proliferating
• Activated CD4+ T cells plays a central role in inducing various
• During foreign tissue recognition, donor APCs transferred during
the operation and bearing foreign MHC molecules can engage
directly with host T cells (direct allorecognition, left),
• or donor cells and cellular debris can be taken up by host APCs and
processed, allowing fragments of foreign MHC peptides to be
presented by recipient APCs bearing self MHC (indirect
allorecognition, right
Effector stage
• The most common effector mechanisms are
• cell-mediated reactions
– Delayed-type hypersensitivity
– CTL-mediated cytotoxicity
• The less common mechanism
– Antibody-complement lysis
– Antibody-dependent cell-mediated cytotoxicit
Time course of graft rejection
• Hyperacute rejection - mediated by preexisting
host’s antibodies binding to donor endothelial
Ags
• Acute rejection - mediated by T cells and
antibodies causing vascular & parenchymal injury
• Chronic rejection – mediated by alloantigen
specific CD4+ T cells, macrophage & cytokines
Hyperacute rejection
• This occurs within minutes or hours after a transplantation
• it is caused by the presence of preexisting antibodies of the
recipient, that match the foreign antigens of the donor, triggering
an immune response against the transplant.
• These antibodies could have been generated as a result of prior
blood transfusions, prior transplantations or multiple pregnancies.
• These antibodies induce both complement activation and
stimulation of endothelial cells to secrete Von Willebrand
procoagulant factor, resulting in platelet adhesion and aggregation.
The result of these series of reactions is the generation of
intravascular thrombosis leading to lesion formation and
ultimately to graft loss
Acute rejection
• Acute rejection is a category of rejection that occurs
between 1 week and several months after
transplantation.
• Acute rejection is thought to result from two
immunological mechanisms that may act alone or in
combination: (1) a T-cell-dependent process that
corresponds to acute cellular rejection, and
• (2) a B-cell-dependent process that generates the acute
humoral rejection.
• These Donor APCs migrate to recipient Lymphoid
system and present foreign HLA to primed Tcells
(CD4, CD8).
• CD4 recognize foreign peptide in the context of Class
II MHC and are crucial in the helper functions (B cell
activation and Antibody production and switch).
• CD8 recognize foreign peptide in the context of
Class I MHC and are associated with cytotoxic and
effector T cell functions.
• When the organ is
transplanted,
alloantibodies are newly
formed by B-cells.
• Elevations in IL-4, -5, and -
6, responsible for B cell
activation and eosinophil
accumulation in allografts,
along with increases in IL-
17, have all been linked to
transplant rejection.
Chronic rejection
• IT is a common characteristic of all solid organ and composite tissue allograft
transplants and usually occurs within 1 year or later after transplantation
• The frequency of chronic rejection is correlated with several risk factors,
including acute rejection episodes, recipient sensitization, insufficient MHC–
matched antigens, recipient age and race, inadequate immunosuppression, hy-
pertension, etc
• Chronic allograft rejection can be caused by antibody-dependent complement
activation and cell-mediated arteritis, leading to the development of interstitial
fibrosis and tubular atrophy.
• The hallmark feature of chronic graft rejection is injury to the vessels’
endothelium. Initial vascular injury initiates an inflammatory cascade that leads
to allograft atherosclerosis and graft fibrosis. Luminal obliteration caused by
blockage of the blood vessels occurs because of the proliferation of smooth
muscle cells that have migrated from the vessel wall and deposited matrix
proteins. Ultimately, fibrosis leads to allograft dysfunction
• It involving the maturation of both T- and B-
lymphocyte responses. Antibodies are directed
at the foreign (nonself) antigens within the graft.
Subsequent deposition of antibody-antigen
complexes leads to targeted destruction of graft
tissue and indirect damage to vascular beds..
Graft vs. Host rejection
• Graft-versus-host disease (GVHD) is a systemic disorder occurring
when immune cells from transplanted tissue recognize the recipient's
body as foreign and attack its cells. GVHD is a common complication
following allogeneic hematopoietic stem cell transplant.
• During transplantation, the donor tissue, usually obtained from a
genetically different individual (an allograft), prompts immune cells in
the graft to recognize the recipient's MHC proteins as nonself,
triggering an immune response between the donor and the recipient.
• Donor cytotoxic CD8 T-cells recognize host tissue as foreign and
proliferate to cause severe organ damage (type IV cytotoxic T-cell
hypersensitivity reaction).
Finding an eligible donor-recipient match
• Rejection can be minimized by carefully matching the donor and
recipient for compatibility prior to transplantation. The better
matched the donor and recipient are the more successful the
transplantation is likely to be. Several tests are commonly done
including:
• ABO blood group compatibility – The donor and
recipient are tested for compatible blood groups.
• Tissue typing – A blood sample is taken from the
recipient to identify the HLA antigens present on
the surface of their cells to help find a compatible
donor.Siblings offer the best donors usually.
• Panel reactive antibody test
– The blood serum of
patients awaiting
transplantation are tested
for reactive antibodies
against a random panel of
cells.
• The more HLA antibodies
present, the higher the
panel reactive antibody
(PRA) level denoted to the
patient, and the greater the
chance of graft rejection.
Cross matching – Blood
samples are taken from both
the recipient and the donor,
and the cells of the donor
are mixed with the blood
serum of the recipient.
If the recipient's antibodies
attack the donor cells, they
are considered a positive
match and transplantation
will not be suitable due to
increased risk of hyper-
acute rejection.
Treatment / Management
1. Hyperacute Rejection: No effective therapy, so prevention is the key by
assuring the ABO compatibility between donor and recipient&Pre-transplant cross-
match
2. Antibody-Mediated Rejection:
The treatment of acute antibody-mediated rejection also depends on the antibody
levels. Higher antibody levels need plasma exchange for the removal of the antibodies.
The following are the different modalities used for AMR:
• Plasma exchange: 3 to 5 sessions daily on every other day are used for antibody
removal, followed by IVIG and rituximab
• IVIG: IV immunoglobulin
• Rituximab: Anti CD20 cell antibody rituximab (375 mg/m^2) is combined with IVIG,
followed by plasma exchange
• Splenectomy: A splenectomy is very rarely an option, but there are anecdotal reports
of successful treatment of refractory rejections
3-T Cell-Mediated rejection:
• Methyl prednisone IV (250 to 1000 mg daily) targeting
T cells, B cells, and macrophages;
4-Immunosupressive drugs
• To reduce the risk of transplant rejection, patients are
treated with immunosuppressive drugs.
• Immunosuppressive drugs are given in two phases;
an initial induction phase involving a high dose, and a
later maintenance phase which involves using the
drug in the long term at a lower dose
REFERNCES
• Moreau, Aurélie et al. “Effector mechanisms of rejection.” Cold Spring
Harbor perspectives in medicine vol. 3,11 a015461. 1 Nov. 2013,
doi:10.1101/cshperspect.a015461
• https://www.rama.mahidol.ac.th/graded/sites/default/files/public/
High_Diploma/handout_HD/handout_HD701/handout_HD64/
Basic_Principle_of_Transplantation.pdf
• https://utkaluniversity.ac.in/wp-content/uploads/2022/06/Transplantation-
immunological-aspects.pdf
• Schmitz, R., Fitch, Z.W., Schroder, P.M., Choi, A.Y., Jackson, A.M., Knechtle,
S.J. and Kwun, J. (2020), B cells in transplant tolerance and rejection: friends
or foes?. Transpl Int, 33: 30-40. https://doi.org/10.1111/tri.13549
