Download Tumor antigens

Lecture Notes for Med. Tech. Class
Transplantation and Rejection
Oct. 2006
C.K.Shieh
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
Genetic Barrier of Transplantation
Clinical Transplantation
• Brain cells
• Gene modified cells
Histocompatability Inheritance
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H-2 as 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.
Transplant Rejection episode I: Host vs. Graft
Transplant Rejection episode II: Graft vs. Host
Tolerance Induction in Transplantation
• Thymic negative selection mediated by dendritic cells
Primary and Secondary Rejection
Role of T Cells in Rejection
Types of Rejection
Hyperacute Rejection
Acute Rejection
Chronic Rejection
Prevention of Rejection
• Tissue matching
• Immunosuppression with anti-mitotic drugs
• Specific immunosuppression (enhancement)
Blood transfusion for kidney transplant patients
Tissue Typing (I): Serotyping
Tissue Typing (II): MLR
Immunological Enhancement: Peripheral Tolerization
Direct and indirect recognition for rejection
器官移植不只是人類長期以來的醫學夢想，也是重要的臨床治療方
法。在世界各國，器官移植的兩個障礙都是：第一、器官來源的困難，
第二、移植器官的排斥問題。為了解決第二個問題，醫學研究者幾十年
來，解決了免疫系統的許多疑問。有些成果，遠超出當初的想像，造就
了現代的免疫學。但是，器官移植的問題仍然沒有完全解決。仍待我們
更進一步的研究和了解。
本節課的重點在了解參予器官排斥反應的免疫細胞。這些免疫細胞
的刺激、調控、和免疫抑制的方法。這些基本控制機轉的了解，將來也
還會是基因治療免疫反應的知識基礎。
Lecture Notes for Med. Tech Class
Tumor Immunology
2006
C.K.Shieh
Tumor Immunology
-Outlines
• Tumor surveillance: the same machinery against virally infected cells used
• Tumor antigen: defined by antibody and cellular immunity
• Evasions of tumor from immune attacks
• How to revive the ineffective immunity against tumors
Lymphocyte Infiltration In and Around Tumors
Both CD4 and CD8 (+) cells are present.
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.
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, inducing leukocyte cell death.
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 and graft versus host disease
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.