1/11/2023

Lecture-32

MIC-317/303; section-1

Transplantation Immunology
Md. Fakruddin, PhD (Fddn)
Assistant Professor
Department of Biochemistry & Microbiology
School of Health & Life Sciences
North South University, Dhaka, Bangladesh
Office- SAC824
Tel:+8801304206807
Email: [email protected]

Immunology MIC317

Learning objectives

By the end of this lecture you will be able

To learn:

1. What is Transplantation.

2. Types of graft rejection.

3. Clinical transplantation.

4. GVHD and Immunosuppressive therapy.

Immunology MIC317

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Transplantation
• Definition: to transfer (an organ or
tissue) from one part or individual to
another
• Transplantation is the process of taking cells,
tissues, or organs, called a ,graft, from one
individual and placing them into a different
individual.
• The individual who provides the graft is called
the donor, and the individual who receives
the graft is called either the recipient or the
host

• Transplantation
– Transfer of cells,
tissues, or organs
• 1st human kidney
transplant
– 1935
– Patient died to mistake
in blood typing

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• Immunosuppressive Agents
• Delay or prevent rejection
• Majority of these have overall immunosuppressive
effect

• New methods being developed

– Inducing specific tolerance to graft without suppressing
other immune responses

Different types of Transplants

 Autograft
○ Self tissue transferred from one part of body to another
 Isograft
○ Tissue transferred between genetically identical
individuals
 Allograft
○ Tissue transferred between genetically different
members of same species
 Most of our transplants
 Xenograft
○ Tissue transferred between different species

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Allograft Rejection
(a) Acceptance of an autograft is completed within 12–14
days

(b) First-set rejection of an allograft begins 7–10 days after

grafting, with full rejection occurring by10–14 days.
(c) Second-set rejection of an allograft begins within 3–4
days, with full rejection by 5–6 days. The cellular infiltrate
that invades an allograft (b, c) contains lymphocytes,
phagocytes, and other inflammatory cells

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• T cells can transfer allograft rejection.

When T cells derived from an allograft-
primed mouse are transferred to an
unprimed syngeneic mouse, the recipient
mounts a second-set rejection to an initial
allograft from the original allogeneic strain.

• T cells play key role in allograft rejection

– Both CD4+ and CD8+ populations present

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The Immunology of Allogeneic

Transplantation
Allogeneic MHC molecules are presented
for recognition by the T cells of a graft
recipient in two fundamentally different
ways
1. Direct and
2. Indirect

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Direct presentation in
transplantation
• Graft dendritic cell is induced to mature, express co-
stimulatory molecules (B7).

• DC in lymph node activates allo-MHC recognizing CD4+

T cells and/or CD8+ T cells

• Activated T cells expand and then home to sites of

inflammation where they find allo-MHC on graft cells and
secrete cytokines/kill graft cells

• This is the critical pathway for CD8 T cell response

Indirect presentation in
transplantation
• Dendritic cells, monocytes, or B cells of host enter sites
of inflammation of graft, pick up antigens (e.g. allo-
MHCs), and load peptides from these allo-MHC onto
their own MHC, migrate to lymph nodes and activate T
cells

• CD4+ T cells are activated and then migrate to sites of

inflammation where they are activated by host
macrophages presenting graft antigens, leads to
inflammatory reaction and tissue damage Also, important
for production of antibodies to MHC molecules

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Clinical Manifestations of Graft

Rejections
• Hyperacute
• Within hours
– Pre-existing recipient antibodies
– Graft never become vascularized
• Acute
• Within weeks
• T cell immune response (CD4 and/or CD8 T cells)
• Chronic
• Months to years
• Mechanism uncertain by DTH

Hyperacute rejection
• Takes place within 24 hours of transplantation
• Serum antibodies react to foreign MHC, triggering
the complement system
• The inrush of neutrophils and the inflammation
causes clot formation in the blood vessels
• The graft dies without being vascularized

But where do
those serum
antibodies
come from?

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Acute rejection
A two-stage process

A good old fashioned

immune response

Within two weeks of

transplantation,
macrophages and
lymphocytes swarm
the tissue, triggering
cytotoxicity,
complement
activation, and graft
cell lysis

The two week delay is

indicative of the TH
activation time

Chronic Rejection
• Even if a graft escapes an immediate
rejection responses, it can undergo
rejection years later

• Tissue typing and immunosuppressive

drugs decrease the likelihood of
chronic rejection, but they have a
long way to go

• If the rejection cannot be managed,

another transplant may be necessary

• Of course, due to the memory and

specificity of the immune system,
subsequent rejections occur even
more quickly and vigorously

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Immunosuppressive Therapy
• . Azathioprine
– Help lower T cell proliferation
• Methotrexate
– Folic acid antagonist – blocks purine synthesis
• Corticosteroids
– Reduces inflammation
• X-irradiation of recipient before grafting
• Antibodies specific for immune cells to keep them at
lower numbers
• Ant- CD3, Anti-CD25, Anti-CD52 and Anti-IL-2

Clinical Transplantation

• Many human diseases and disorders are

caused by defects in organs and tissue

• Transplanted organs can replace organs

that are defective or damaged by disease.

• Improved surgical technique has made

many different types of tissue grafting
possible

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Clinical Transplantation

Milestones in Transplantation
• 1682(!) – bone from a dog is used to repair a human skull
• 1881 – earliest skin grafts (some using frog skin)
• 1930 – Karl Landsteiner awarded Nobel Prize for discovery
of ABO blood groups
• 1945 – P.B. Medawar publishes a paper linking graft
rejection and the immune system
• 1954 – first successful kidney transplant between identical
twins
• 1967 - first successful heart transplant
• 1990 – first living-donor lung transplant
• 1992 – a patient receives a baboon liver and survives for
two months
• 1995 – An AIDS patient receives a bone marrow
transplant from a chimpanzee
• 2002 – first liver transplant (between identical twins)
performed without immunosuppresion

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Graft-versus-host disease (GVHD)

• Lymphocytes from the donor

are carried by the organ into
the body of the graft
recipient

• If the recipient is
immunocompromised, the
foreign lymphocytes can
attack his tissue, resulting in
skin rashes, intestinal
problems, organ failure, and
death

• Liver, spleen, and bone

marrow transplants all carry
the risk of GVHD

Barriers to Medical Transplant

Difficulties posed by the immune system
• The necessity of MHC matching makes it
harder to find compatible organs
• Repeat graft recipients reject new organs
faster and more vigorously with each new
transplant

Shortage of available organs

• Many transplantable organs can only be taken
from cadavers
• Organs must also be matched for size and
condition

Solutions?

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Immunosuppressive Therapy
Non-specific
• Drugs that interfere with the
immune response

• This attenuates the

rejection of donor tissue

• Decreased immune
responsiveness increases
susceptibility to pathogens
and cancers

• Current therapies involve

using multiple drugs in low
doses: the goal of this is to
minimize side effects while
still preventing rejection

• Many immunosuppressives
are derived from
fungi…why?

Cyclosporin A

Immunosuppressive Therapy
Specific
• Treatments that produce an immunodeficiency specific to
the donor alloantigens – an artificial hole in the repertoire

• Monoclonal antibodies can block T-cell activation and

binding, extending the life of transplanted organs

• Soluble fusion proteins can be made with block

costimulatory signals necessary for T-cell activation

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Xenotransplantation
Xenotransplantation – the transfer of tissue
from one species to another

• Usually refers to the implantation of animal

tissue in humans

• Many different types of tissue may be

transplanted

• Using animals for organs would provide a

vast new source of organs for humans

Clinical Aspects
• Attempts at kidney, heart, liver, and bone marrow
transplants from primates into humans have met
with little success

• The earliest xenotransplantation of a chimpanzee

kidney into a human took place in 1964

• In 1993, T.E. Starzl performed two liver transplants

from baboons into patients suffering from liver
failure (both died within 70 days)

• Pigs have also been considered as a source of

organs, especially kidneys

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Problems with Xenotransplantation

• Even with immunosuppression, the
foreignness of animal tissue provokes a
vigorous immune response

• Viruses and diseases which have no ill

effects in animals have the potential to
cause serious illness in humans

• Animal retroviruses may combine with

human variants, producing dangerous
new pathogens

Solutions?
• Animals bred with human
histocompatibility genes (transgenic
animals) would have organs
immunologically indistinguishable
from human organs

• Other transgenic organs might

produce proteins that prevent
destruction by the complement
system

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Any Questions?
Beauty of Tenasplantation

Vacanti Mice

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