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Rejection of kidney
transplant
Dr. Mohamed Sakr, M.D.
Medical Microbiology and Immunology
 Kidney transplantation

Kidney transplantation is the

treatment of choice for patients
with end-stage renal failure.
The transplanted organ is
predisposed to allograft rejection
related to immunologic injury.
 Categories of allograft rejection

Descriptions of the rejection

reactions as might be observed,
after transplantation of a kidney;
• Hyperacute rejection
• Acute rejection
• Chronic rejection
• Mechanism: It is a result
of destruction of the Hyperacute Rejection
transplant by preformed
antibodies to incompatible
MHC antigens.
These cytotoxic antibodies
activate the complement
system, followed by platelet
activation and deposition,
causing swelling and
interstitial hemorrhage in the
transplanted tissue, thereby • Time: occurs within minutes
decreasing the flow of blood to a few hours of
through the tissue.
transplantation.
Hyperacute Rejection

Such antibodies have been produced in the recipient prior to

transplant. These preformed antibodies are generated as a
result of previous transplantations, blood transfusions, or
pregnancies.
• Sequalae: Thrombosis with endothelial injury and
fibrinoid necrosis is often seen.
• Clinical features: The recipient may have fever,
leukocytosis, and will produce little or no urine. The urine
may contain various cellular elements, such as
erythrocytes.
 Acute Rejection
• Acute rejection is seen in a recipient who has not previously
been sensitized to the transplant.
Types: A- Antibody mediated or humoral acute rejection,
B- Acute cellular rejection .
A) Humoral acute rejection usually occurs within the first 3
months following transplantation. this manifests as a sudden
decline in kidney function. Donor-specific antibody (DSA)
is detected and C4d is deposited on the endothelium of the
kidney due to activation of complement.
 Acute Rejection
B) Acute cellular rejection
usually occurs 1–6 weeks
to several years following
transplantation when doses
of immunosuppressive
drugs are lowered. In cell-
mediated immunity, intense
infiltration of lymphocytes
and macrophages, is taking
place at the rejection site.
 Acute Rejection
Clinical features: Enlargement and tenderness of
the grafted kidney, a rise in serum creatinine level,
a fall in urine output, decreased renal blood flow,
and presence of blood cells and proteins in the
urine are characteristic.

Treatment: Acute rejection may be reduced by

immunosuppressive therapy, for example, with
cyclosporine and other drugs. corticosteroids is
used for treatment of both types of acute rejection.
 Chronic Rejection
• Time: occurs in allograft transplantation months or
years after transplantation and characterized by
slow, progressive renal failure.
• Mechanism: Chronic rejection caused by both
antibody and cell-mediated immunity
• Subclinical microvascular inflammation, associated
with antibody-mediated rejection, which can be
with or without complement activation, predicts
progression to chronic rejection.
• Antibodies targeting angiotensin type 1 receptor, in
addition, antibodies against endothelin type A
receptor.
 Chronic Rejection
• Chronic reaction is accompanied
by chronic delayed type
hypersensitive, proliferative
inflammatory lesions of the small
arteries, thickening of the
glomerular basement membrane,
and interstitial fibrosis.
• Because the damage caused by
immune injury has already taken
place, immunosuppressive
therapy at this point is useless.
 Immune response against grafts
• Two stages:
(1) a sensitization phase, which occurs shortly
after transplantation when antigen reactive
lymphocytes of the recipient proliferate in
response to alloantigens on the graft , and
(2) a later effector stage, in which immune
destruction of the graft takes place.
 Immune response against grafts
The Sensitization Stage of Graft Rejection
During the sensitization phase, CD4 and CD8 T cells
recognize and proliferate in response to alloantigens
expressed on cells of the foreign graft.
• Direct recognition: MHC-peptide complexes on
Donor APC are recognized directly by recipient T
cells without processing by recipient APC
• Indirect recognition: Foreign MHC and other
alloantigens are processed by recipient APC and
presented to recipient T cells
 Immune response against grafts
The Sensitization Stage of Graft Rejection
 Effector Stage of Graft Rejection
Cell mediated immunity
The most common are cell mediated reactions and
involving an influx of immune cells into the graft .
Among these are T cells, especially CD4,and APCs, often
macrophages. the infiltration in many cases resembles
that seen during a DTH response, in which cytokines
produced by T cells promote inflammatory cell
infiltration.
CD8 T cells
• Recognition by host CD8 T cells of either foreign class I
alloantigens on the graft or alloantigenic peptides cross-
presented in the context of class I MHC by DCs can
lead to CTL-mediated killing.
 Effector Stage of Graft Rejection
CD4TH cells
IL-2 and IFN- produced by TH1 cells promote:
T-cell proliferation (including CTLs), DTH responses,
and the synthesis of IgG by B cells, with resulting
complement activation.
Interferons and TNFs
• Encourage the expression of MHC class I and class II
molecules to increase surface expression of proteins.
TH2 and TH17 cells
• Elevations in IL-4, -5, and -13, responsible for B-cell
activation and eosinophil accumulation in allograft s,
and in IL-17, have all been linked to transplant
rejection.
 Effector Stage of Graft Rejection
Antibody-mediated complement lysis and
destruction by ADCC.
• These antibodies are often directed against
donor HLA molecules or endothelial antigens.
The hallmarks of this response, are the
activation of complement and deposition of
C4d, especially among endothelial cells lining
graft capillaries.
Human leukocyte antigen
(HLA) testing

• HLA testing is a blood test

that identifies antigens on the
surface of cells and tissues. It
is used to match a transplant
recipient with a compatible
donor.
 Human leukocyte antigen (HLA) testing

1- HLA typing
2- HLA Antibody Testing
3- Mixed lymphocyte reaction
 HLA typing
Determination of HLA phenotype for donor &
recipient
• Microlymphocytotoxicity assay for HLA
typing
• HLA typing by molecular techniques
 Microlymphocytotoxicity
assay for HLA typing
• Lymphocytes are tested with a
panel of sera containing well
characterized HLA-specific
alloantibodies. Each serum is
placed in a microtiter well.
After a short incubation, rabbit
serum is added as a source of
complement and the cells that
have bound the alloantibody are
lysed making them permeable
to the fluorochrome ethidium
bromide. The wells containing
the lysed cells are easily
discriminated.
 HLA typing by molecular techniques
• Polymerase chain reaction
(PCR) based HLA typing
techniques allow the
determination of DNA
sequence variations.
 2- HLA Antibody Testing
Detection of preformed antibodies
• HLA cross match
• HLA antibody screen
 HLA cross match
• The white cell cross match: The recipient
serum is incubated with specific donor,s
lymphocytes. A positive cross match is
contraindication for organ transplant.
• Flowcytometry
• ELISA
 HLA antibody screen
Mixed lymphocyte cross match
(Percentage Panel Reactive Antibody %) or PRA

• The recipient serum is mixed with a randomly

selected panel of 60 donor lymphocyte samples
to measure their activity against the panel.
• If the patient serum reacts with 30 out 60
samples, the patient PRA is 50%.
 3- Mixed lymphocyte reaction
• A test prepared by mixing lymphocytes
isolated from two different individuals
whereby one of them is usually the potential
donor (killed by irradiation) and the other one
is the potential recipient of a transplant.
• Different MHC antigens on the surface of
donor lymphocytes will activate the recipient
lymphocytes. The result is activation of DNA
synthesis (the measurement is based on
incorporation of tritium labelled thymidine).
 3- Mixed lymphocyte reaction

• More proliferation
of lymphocytes
indicating an
unsatisfactory
match.