Download Transplantation Immunology

Transplantation, Rejection and Immunity to Cancer （2/5）
3/16/2015
C.K.Shieh
§ By investigating the barrier of tissue transplantation between different individuals,
we came to get hold of a plethora of information that is not only important for the
clinical practice of organ transplantation but also critical for other immune
responses. From this lecture, we will understand the molecular basis of
histocompatibility (feasibility of tissue transplantation) and the cells that are
involved in this immune-mediated barrier.
Transplantation Immunology
• Study of tissue transplantation lead to the discovery of MHC molecules and the
subsequent discovery of T cell receptor.
• Organ transplantation is now an important clinical practice.
Saintly Transplantation
by Sts. Cosmas and Damian
the 3rd Century
Immune barrier between individuals with different inheritance is the main limiting
factor of clinical transplantation
 Humoral immune barriers: e.g. ABO incompatibility
 H-2 (MHC)
 MHC class I molecules are expressed on most cells in the body, while MHC class II
are usually expressed only on antigen presenting cells.
Tolerance Induction in Transplantation
• Thymic negative selection mediated by dendritic cells
Host vs. graft reaction
First and Second-set Rejection
Previous sensitization by alloantigens leads to rapid (secondary) rejection.
rejection can be transferred with lymphocytes from sensitized animals.
This
The genetics of allo-recognition
The gene determining allo-rejection (H2 or major histocompability gene (MJC)) is very
polymorphic and codominantly expressed. The recognition of allo-MHC by TCR is
responsible for almost all strong rejection reactions. There are evidences from human
transplantation showing that indirect antigen presentation may contribute to late rejection
of allografts.
Types of Rejection
Hyperacute Rejection
Acute Rejection
Chronic Rejection
Accelerated rejection
Prevention of Rejection
• Tissue matching
• Immunosuppression with immunomodulators and anti-mitotic drugs
Glucocorticosteroids, cyclosporine, tacrolimus (FK506), azathioprine and others
Cyclosporine and tacrolimus are the so called “T cell-specific” immunosuppressants.
The binds to their respective receptors and inhibits the enzymatic activity of the
calcinurin ( a protein phosphatase) and lead to suppression of IL-2 dependent cell growth.
• Specific immunosuppression (enhancement)
Blood transfusion for kidney transplant patients
Tissue Typing (I): Serotyping
Tissue Typing (II): MLR
Graft vs. Host Reaction
Bone marrow transplantation and graft versus host disease (GVHD)
Immunological Enhancement: Peripheral Tolerization and regulatory T cells
Figure: Direct and indirect recognition for rejection
Tumor Immunology
2016
C.K.Shieh
§ In this lecture, we will discuss about how immune cells recognize cancer cells and
keep our body tumor-free. Both innate immunity and acquired immunity
participate in this process which has been extensively investigated for potential
approaches to manipulate.
Tumor Immunology
-Outlines
• Tumor surveillance: the same machinery against virally infected cells is used
• Tumor antigen: defined by antibody and cellular immunity
• Evasions of tumor from immune attacks
• How to revive the ineffective immunity against tumors
Specific Immune Responses Are Present in Chemical-induced Tumors
Tumor-specific immune responses can be transferred by T cells (adopted immunity).
This fact was proved only after syngeneic animals became available and valid controls
were possible.
Tumor antigens
Several approaches have been used to search for tumor antigens in human cancer patients
• T cell tumor antigens: Specific antigen peptides were purified based on their activity to
stimulate tumor specific T cell clones (derived from cancer patients).
• Tumor inducing mutations as tumor antigens: Mutations that lead to cancer
formation are distinctions that immune cells can use to recognize tumor cells. Many
of these mutations have been proved to be tumor antigens.
• B cell tumor antigens: Serum from cancer patients were used to clone tumor antigens
from cDNA library prepared from tumor cells (SEREX).
Many of these antigens identified from different approaches proved to be on the same
tumor molecules.
Viral antigens as tumor antigens
Viruses and Cancer Formation
Some persistent viruses (e.g. EBV) are known to induce human cancers.
immunity is apparent in these cancers and other virus induced-cancers.
Immunodeficiency predisposes patients to these tumors.
Anti-tumor
A peculiar bacterium, H. pylori was associated with the occurrence of human stomach
cancer. As this bacterium does not transform human epithelial cells, the mechanism for
cancer induction appears more complex than carcinogenic viruses.
How Tumors Escape Immune Destruction
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Lack of MHC class I in a prostate carcinoma
MHC class I loss in tumor cells makes them less susceptible to CTL but more
vulnerable to NK killing.
Immunosuppressive signal: suppressive cytokines, e.g. TGF-
Lack of costimulation (e.g.B7): inducing antigen specific anergy
Expression of suppressive signal: e.g. FasL, PD-L1inducing leukocyte cell death and
immunosuppression, stimulation of CTLA-4 on CTL also inactivate the anti-tumor
activity.
How to Revive the Immune Responses:
Breaking the Immunological Silence: Providing the Costimulation
•B7 transfected tumor cells as cancer vaccine
Adjuvants
•Since 1920’s, certain substances were added to immunogens to increase desirable
immune responses.
•The biological effects are to be a depot for immunogen or induce cytokines.
•A lot of interest and experiments are going on to use cytokines to increase responses to
vaccines in the future.
Cancer Vaccines
•Coley used bacterial filtrate to stimulate immune system in order to reject tumors one
century ago.
•The idea of non-specific immune stimulation has attracted enormous amount of
imagination and efforts from both the scientific community and general public. Little
success was documented.
•New strategies based on insights in immune response to tumors will be used to design
approaches for “therapeutic vaccines”.
•HSP-peptide purified from tumors as vaccines.
•Dendritic cells as strong antigen presenting cells for tumor antigens.
“Immunotherapy” for cancers
•TIL (tumor infiltration lymphocytes) as an adaptive immunotherapy for cancers.
•Graft versus tumor (good) and graft versus host disease (a complication of bone marrow
transplantation)
Immunodetection for Cancer Diagnosis
Detection of metastasis at gross and cellular levels
Serum tumor proteins: CEA, -fetal protein are embryonic proteins that are expressed in
adult tumors. These markers become useful for tumor detection, progression or
recurrence.