Immune Response to

Transplantation
TRANSPLANTATION IMMUNOLOGY

• Transplant or Graft: Transfer of living cells, tissues and

organs from one part of the body to another or from one
individual to another.
• The cells of an individual express a unique set of
membrane antigens – alloantigens – which
immunologically define a person’s cell type.
• A major limitation to the success of transplantation is the
immune response of the recipient to the donor tissue.
• The speed at which graft rejection occurs is related to
the degree of antigenic differences b/n donor & recipient
• Organ transplantation involves manipulating a complex
collection of cells & tissues types.

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 Transplantation Immunology

Why do we need transplant?

Basically to restore function when:
– Organ or tissue is irreparably damaged as a result of
disease or injury.
– Organ or tissue is congenitally absent or defective.

• Donor - The individual from whom tissue/organ is taken

• Recipient - The individual in whom the tissue/organ is
applied
• Most common transplantation is blood transfusion.

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 Transplantation Immunology
• Types of grafts: Classification based on genetics
1. Autograft: self to self
– Transplant from one area to another on the same
individual (e.g: skin graft in burn)
– No immune response will occur against it.
– This does not require immunosuppressive therapy.
2. Isograft/Syngenic graft:
– Graft between syngenic individuals [as seen in identical
(monozygotic) twins]
– Donor & recipient have identical genetic constitution &
are histocompatible; No rejection.
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 Transplantation Immunology

3. Allograft:
– Graft between genetically dissimilar individuals of
same species
– Recipient recognizes graft foreign & is immunologically
rejected.
– Donor & recipient histoincompatible, e.g. blood
transfusion

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 Transplantation Immunology
4. Xenograft/heterograft:
– Graft between 2 different species.
– Have a very poor prognosis because of the presence of
cross-species reactive antibodies that will induce hyper
acute rejection
– Immune response destroy & reject graft immediately
– Rejection process is highly intense.
Donor-recipient matching
• Autograft & isograft - not rejected due to antigenic
identity
• In allografts, donor-recipient couple matching
necessary

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 Histocompatability Antigens
• Immune response against transplants depends on the
presence in the grafted tissue of antigens that are
absent in recipient and hence recognized as foreign
Transplantation antigens: MHC
• Class I antigens: constitutively expressed on surface
of most cells
• Class II antigens: expressed on cells of lymphoid
system
Nomenclature
• HLA (human) class I: A, B, C; class II: DR, DQ
• H-2 (mouse) class I: K, D, L; class II: IA, IE
 Transplantation Immunology
Rejection: evidences of rejection
– The speed of rejection depends on the tissue involved &
degree of antigenic differences b/n donor & recipient
– The greater the difference, the faster & more acute the
rejection will be.
– Skin grafts are rejected faster than kidney or heart
transplants.
 Transplantation Immunology

Graft rejection
• Analogous to primary & secondary Ab response.
1. First set rejection:
– There is initial vascularization of the graft & good
circulation of the graft, but after 11-14 days, marked
reduction in circulation, infiltration of the graft bed with
mononuclear cells, graft becomes necrotic & sloughs.
– Lymphoid cells & antibodies involved,
– Reaction is chronic, slow & progressive – delayed
rejection reaction.
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 Transplantation Immunology
2. Second set rejection:
– Hyperacute or immediate rejection response elicited
when graft is applied to recipient from the same donor
– Accelerated rejection within 3-6 hrs occurs.
– Plasma cells, cytolytic leukocytes & complement
mediated by antibody - lysis involved.
– Vascular supply destroyed – thrombosis.

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 Transplantation Immunology
• Mechanisms for allograft rejection:
1. Memory of immunological process (sensitization)
2. Specificity
3. Transferred sensitivity
4. Genetic control at HLA
5. Dendritic and other cells in graft may act as APCs.
• Lymphocyte but not Ab can transfer allograft immunity
• Both T-cells - CD4 & CD8 are involved in graft rejection.
• Both delayed type hypersensitivity & cell-mediated
cytotoxicity reactions have been implicated.

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 Transplantation Immunology
Two stages involved:
a. Sensitization phase.
– CD4 & CD8 T cells recognize alloantigens.
– Both minor & MHC are recognized

b. Effector phase.
– Delayed type hypersensitivity.
– CTL mediated cytotoxicity.
– Antibody – compliment lysis.
– Antibody dependent cell-mediated cytotoxicity (ADCC)

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 Transplantation Immunology

Clinical stages of rejection

• Depending on time of onset, clinical manifestation &
pathological changes, rejection is classified into 3:
1. Hyperacute rejection:
 Appears immediate within mins - hrs (<24 hrs)
 Ab-mediated cytotoxic response to the fixation of Abs
to specific class I Ags on vascular endothelium due to
preformed / Pre-existing cytoxic Abs (IgG).
 Abs responsible for hyperacute rejection include Abs to
ABO blood group Ags.
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 Transplantation Immunology
• Recipient was sensitized to the histocompatible Ags by
previous multiple blood transfusions, transplantations
• Characterized by thrombotic occlusions, sludging of
blood cells & hemorrhage of the graft vasculature
• Abs activate the complement system then platelet
activation & deposition causing hemorrhaging & swelling
• It is irreversible,
• It is resistant to immunosuppressive therapy.
Treatment
– No treatment
Prevention
– Pre-transplant cross match.
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 Transplantation Immunology

1. Preformed Ab, 2. Complement activation,

3. Neutrophil margination, 4. Inflammation,
5. Thrombosis formation
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 Transplantation Immunology

Accelerated Graft Rejection

• A subtype of hyperacute rejection, is a cellular immune
response.
• Antibody produced immediately after transplants.
• It can occur when the recipient has been exposed
previously to low levels of donor tissue Ags & makes a
rapid memory response when the donor organ is
transplanted.
• Accelerated acute rejection manifests within a few
days to a few weeks following transplantation, and
leads to allograft loss.

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 Transplantation Immunology
2. Acute: antibody or cellular mediated
• Seen in recipient that has not been previously
sensitized to the transplant
• Mediated by T cells (CD4+, CD8 T-Cells) & humoral Ab
response - a result of their direct recognition of
alloantigens expressed by the donor
• Caused by mismatched HLA Ags that are present on
all cells or insufficient immunosuppressive treatment
• Acute rejection is a cellular immune response involving
macrophages, mononuclear, cytotoxic & Th cells,
cytokines (monokines & lymphokines)
• Time: weeks. Reduced by immunosuppressive therapy

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 Transplantation Immunology
a. Acute early:
• Appears within 10 days after transplantation
– Cellular infiltration, rupture of capillaries, mediated by
Type IV hypersensitivity reaction
– Involves T cell mediated reactions.
– Manifestation: Fever, chills, oliguria, etc
b. Acute late:
– Appears within 11-21 days.
– Occurs in immunosuppressed recipients.
– Abs & complement cause vascular damage in
glomerular capillary – platelet aggregation
– Respond to immunosuppressive therapy

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 Transplantation Immunology

1. T-cell, macrophage and Ab mediated,

2. Myosite & endothelial damage,
3. Inflammation

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 Transplantation Immunology
3. Chronic (late):
– Occurs within months-years in most solid organ
transplants, e.g. Heart, Kidney, Lung, Liver
– It is associated with sub-endothelial deposits of Igs & C3
on GBM – immune complex due to Type III
hypersensitivity reaction.
– CD4, CD8 (Th2), macrophages are involved
– Characterized by fibrosis & vascular abnormalities with
loss of graft function over a prolonged period.
– It is unresponsive to immunosuppressive therapy.
– Pts should be put under – anti-inflammatory,
antimetabolite therapy

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 Transplantation Immunology

1. Macrophage – T cell mediated

2. Concentric medial hyperplasia
3. Chronic DTH reaction

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 Graft-versus-host Disease (GvHD)

• When competent lymphoid cells are transferred from

donor to recipient, the grafted cells survive, recognize
host Antigens, react with them & reject them causing
GvHD.
• The main effectors are donor T cells (mature T cells),
which are activated in the presence of co-stimulatory
molecules by a storm of pro-inflammatory cytokines.
• GvHD is major problem for bone marrow transplant - a
common complication of allogenic bone marrow
transplantation & transfusions.

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 Graft-vs-host Disease
• The recipient is immunologically disparate – i.e.
histoincompatible
• The recipient is immunocompromised & therefore
cannot destroy or inactivate the transplanted cells.

Possible reasons leading to GvHD:

• Immunologically anergic subjects receiving bone marrow
grafts – e.g. radiation accidents or radiation therapy

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 Graft-vs-host Disease
The 2 forms of GvHD:
1. Acute GvHD:
• First 3 - 6 months
• Characterized by epithelial cell death in the Skin, GIT or
obstructive Liver dysfunction.
• >60% develop
• Described as dermatitis, hepatitis & enteritis (diarrhea)
developing within 100 days of allogeneic
hematopoietic-cell transplantation (HCT)
 Graft-vs-host Disease
2. Chronic GvHD:
• Develope after day 100; i.e. 12-18 months post
transplant
• Characterized by atrophy & fibrosis of one or more of
these same target organs as well as the lungs
• Autoimmune manifestations of skin, GI, Liver & Lung
• Develop in 30-40% of cases
• GvHD reaction is characterized by fever, pancytopenia,
weight loss, rash, diarrhea, hepatosplenomegaly, death

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 Graft-vs-host Disease

GVH disease in humans

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 Graft-vs-host Disease
Complications of transplantations: Infections
1. Early complications:
– Potentially life threatening
– Main complication in first 30 days
– CMV infections have high mortality (Give prophylaxis)
2. Late complication:
– Immune function takes 1-2 years to fully recover.
– Later opportunistic infections common, including
Pneumocystis carinii & herpes zoster
– Prophylaxis required for 6-12 months

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 Graft-vs-host Disease
• Veno-Occlusive Disease (VOD)
• Obstructive liver disease due to microthrombi in liver
venules in patients with previous liver disease at
greater risk
• No good treatments

Methods to overcome GvHR:

• Use autologous bone marrow.
• Treat bone marrow to deplete T cells
• Use umbilical cord blood

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 Graft-vs-host Disease
Laboratory Tests
• ABO & Rh Blood typing
• Tissue typing (HLA Matching) - lymphocyte culture
• HLA-A and HLA-B
• HLA-DR
• (Lymphocytotoxicity test)
• (Mixed leukocyte reaction)
• Screening for Presence of Preformed Antibodies to
allogeneic HLA
• Cross matching: check for pre-formed Abs
 Graft-vs-host Disease
Tissue typing
• Microcytotoxicity assay – Known antibody to WBCs of
donor / recipient – Complement mediated lysis if Ab
present on cell surface
• Mixed lymphocyte culture (MLC) – Irradiated donor
lymphocytes (stimulants) – Incubated with recipient
lymphocytes
• Flow cytometry cross typing
• DNA analysis Genomic typing (very precise, many
subtypes)
 Therapy of Allograft Rejection

Therapy of Allograft Rejection

a. Immunosuppressive Therapy:
– Cyclosporine, azathioprine, cyclophosphamide
– IV administered corticosteroids, such as prednisone,
are the standard of care in acute GVHD
b. Induction of Immune Tolerance:
– Inhibition of T cell activation
• Soluble MHC molecules
– Th2 cytokines
• Anti-TNF-α, Anti-IL-2, Anti-IFN-γ mAb

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 Prevention
Prevention:
– Prophylaxis against GvHD begins day +1 with
immunosuppressive agents – e.g. Cyclosporine,
methotrexate, mycophenelate

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