Tumor and Transplant Flashcards
Tumor and transplants - what is common
The immune response for the 2 are pretty similar
Ipillimumab
Anti CTLA4 antibody
Nivolumab
Anti PD-1 antibody
When is Nivolumab used
Non small cell lung carcinoma and melanoma
Adjuvents
Agents that cause inflammation
Sipuleucal T
The idea over here is that patients with metastatic castrate resistant prostate cancer have their dendritic cells extracted from them, shipped to a company, the company incubates them in GM-CSF, exposes them to an antigen called the PAP (Prostate Acid Phosphatase). Then these dendritic cells are sent back and infused in the patient and this causes an immune response to develop against the cancer.
Bi specific antibodies
These promote tumor immunity. In this antibody we have different light chains and heavy chains linked together such that one half of the antibody targets the tumor cell whereas the other half targets the T cell (specific for CD3 protein or NK marker like CD16). This causes the tumor cells and T cells to come in close proximity promoting tumor destruction.
You can also have trispecific so the FC region can be made to bind to NK cells and the tumor cell can be made to be surrounded with NK cell and T cell.
Chimeric antigen
One of the problems when dealing with tumors is that tumors down regulate their MHC so the T cells cant identify them.
This problem can be solved by making single chain antibodies (scFv). Here the portion of the antibody that binds to antigen is fused with the zeta chain of the TCR. This whole complex is placed into the T cells to repalce TCR. This then allows the T cells to detect antigens without having to require MHC presentation and now they can go and kill cancer cells.
Very successful in lymphoma treatment.
Syngenic
Genetically identical
Congenic
Identical except for one locus
Allogenic
Different members of the same species
Xenogenic
Members of different species
Autologous transplantation
Transplantation within the same individual like skin grafts, HSCTs
Allotransplantation
Most common
Xenogenic transplantation
Xenografts
What is the antigen observed in organ transplant
MHC, there are minor histocompatibility complex - allelic forms of normal proteins that differ in people
What are the mechanisms of organ rejection
Adaptive, T cells and antibodies
What is the biochemical basis of transplant rejection
There is a change in the affinity of MHC-TCR interaciton these 2 interact more strongly now which leads to development of an immune response. Remember the low affinity model of thymic selection which requires that if T cells dont bind to MHC loosely so that they dont trigger an immune response
What are the 2 ways body identifies the foreign organ after a transplant
- Direct allorecognition: T cells go into the transplant organ, recognizes the transplanted organ and mount an immune response towards it
- Indirect allorecogntion is when there is cross presentation so the APC goes into the transplant, engulfs one of the cells and presents the antigen to T cells. He called this process cross presentation.
What 2 immune functions are significant in terms of cross presentation
- Viral infections
2. Tissue rejection
How can we predict transplant rejection
Mixed lymphocyte reaction: Mix the T cells of the recipient with the irradiated donor cells (we need to kill the donor cells so they dont start an immune response). If the recipient T cells are activated then there will be T cell infiltration and proliferate which can be checked for.
What are the 3 types of rejections
- Hyperacute
- Acute
- Chronic
Hyperacute
Malpractice, very fast response.
The immune response is adaptive, however the immune response is pretty damn fast that suggests there are pre existing antibodies.
1. Antibodies could exist from prior trasnfusion
2. Activates compliment and blood clothing mechanisms
Acute
CD8 T cell mediated:
- Targets graft or blood vessels within the graft
- Antibodies also contribute to vascular rejection, role of antibodies is unclear in chronic and acute
Chronic
From hyperactue to chronic we move from more of a type II reactions to a type IV reaction.
So here the T cells kick in:
1. Th1 mediated response
2. Antibodies and compliment system activation, role is unclear
3. Progressive loss of graft tissue
4. Fibrosis and arteriosclerosis of graft tissue (narrowing of the vessels to the graft).
Chronic in inevitable, happens over the years.
Therapy for graft rejection
Immunosuppression:
- GCs.
- Cyclosporin
- Mycophenolate
- Rapamycin
- Thymoglobulin - cocktail of antibodies, target T and B cell and also attacks the antibodies.
What is HSC transplantation used for
Used for primary immunodeficiencies and after chemotherapy for cancer
What markers does HSCs have
CD34
Describe HSCs transfer
- Space created before injection - maybe by high dose chemotherapy
- Isolate CD34 cells
- Treat the donor with G-CSF so CD34 cells become immobilized into the blood, then we can harvest them from the blood
Risks of HSC transplant
- Graft failure
- Delayed engraftment; hemorrhage and anemia
- Opportunistic infections - reactivation of CMV, EBV, bacterial pneumonias and fungal infections
- Tumor reoccurence
- GVHD - Graft versus Host disease, the major problem, mortality is 50%
How do we consider the directions of immune response in solid tissue transplant and HSC transplant
In solid tissue transplant the recipient’s immune system attacks the graft whereas in HSC the donor’s immune system attack’s the body, this is called graft vs host disease.
When evaluating the MHC’s considering the directionality is critical
Requirements for graft versus host disease (GVHD)
Billingham’s postulates:
- Graft must contain immunologically competent cells. There can be special circumstance where this has to be understood well as in liver trasnplants this can happen as live has many macrophages in there to protect it (kupfer cells)
- Recipients must have tissues and antigens that are not expressed in the donor
- Recipient must be not be able to mount an effective immune response to the graft to destroy the transplanted cells
What are these relevant to
HSCT and blood products in infants, thats why the blood is irradiated before given to infants
Categories of GvHD
Acute and Chronic
Acute
Phase 1: We destroy the CD34 cells of the recipient to make room for the new CD34 cells to come in and thrive. in order to do this there is myloablative therapy given which is highly toxic and triggers release of cytokines such as TNF and IL-1
Phase 2: Some of the donor’s CD4 cells are also given to the recipient to prevent reactivation of EBV, CMV and prevent opportunistic infections even though these CD4 cells are going to cause GVHD.
Phase 3: The donor’s CTL, NK cells and monocytes respond to the cytokines and cause GVHD
What is the time frame for acute and chronic
More than 100 days is chronic
Chronic
3 phases:
- Progressive - continuation of GVHD
- Quiescent - presence of continued GVHD with previosuly resolved GVHD
- De novo - New onset of GVHD
What is the MOA of chronic GVHD
- Th1 cell mediated immune response
- B cell are also involved.
- Organs involved are GI, Skin, thymus, BM, lung and bone
Treatment for gvhd
- Steroids
- methotrexate
- cyclosporin
- mycophenylate
- Anti CD25 which is Daclizumab
