Lecture 9: Immune Responses to Stem Cell Transplantation Flashcards
Describe autografts
Took cells from mouse and put them back in the mouse.
Hope to do this with IPS cells in humans.
(Least discordant)
Describe isografts
Inbred mice strains
Done with genetically similar mice
one mouse to another genetically similar mouse
Identical twins in humans would be the equivalent example
Describe allografts
Done in genetically different mice
Two family members (in human example).
Describe xenografts
Across species
Mouse to human
(Most discordant)
As discordance between donor and host ____ so does the risk of ___
1) increases
2) rejection
Why do stem cell scientists need to perform xenotransplants?
To translate preclinical findings toward eventual therapies we need to identify and test the efficacy of human cells.
You can’t just do that in humans first without testing the cells in animal models.
What is the innate immune response?
-The first line of defense
-Lacks specificity
-Provides a physical barrier (ex. skin)
-Recruits other immune cells to a sight of infection or injury.
-Present antigens to adaptive immune cells.
-Remove pathogens and debris by phagocytosis.
What is the adaptive immune response?
-Provides specificity
-Recognition of specific non-self antigens (typically proteins that are not going to hurt their own body).
-Tailored response to eliminate specific pathogens or infected cells.
-Establishment of immunologic memory (ex. vaccines).
Xenograft rejection is mediated by ___ , ____ and ____ cells.
1) B cells
2) T cells
3) NK cells
However the ___ immune system responds first and helps to activate the ___ cell response
1) innate
2) T cell response
Do people ever receive xenotraplsants?
Yes,
Pig heart valve transplants are quite common.
This is because pig valves are made of mostly cartilage and not immunogenic so patient on immunosuppressants can be weaned off them after a year.
Ongoing trials are testing pig islet cells for transplantation for diabetes.
1984: Baby Fae received a baboon heart transplant for hypoplastic left heart syndrome. The baby survived for 21 days.
What are ways to achieve xenotransplantation?
1) Immune suppression (needs to be on immunosuppressants because patients are at higher chances of getting infections) (Calcenurin inhibitors block the activation of T cells).
2) Immune deficient animals (No strong immune system. Could get SCID: severe combined immunodeficiency disorder).
3) Humanized models: Add in hematopoietic stem cells or blood or progenitor cells and transplant to mouse so it makes human cells.
What is likely the optimal way to study long term human stem cell engraftment?
Use immune deficient mice
They lack T cells, B cells, and NK cells but they have normal lifespans when housed in sterile conditions.
Long term transplantation into genetically immune deficient mice can sometimes reveal important safety concerns like tumors.
Potential problems with using immune deficient animals.
Xenotransplantation in immune deficient mice will not really model an isograft or allograft of human cells in a human.
This is because human and mouse immune systems are quite different.
There is also risk of tumors developing in mice and invading adjacent tissues.
What are the conclusions of lecture 9?
-Xenotransplantation can use pharmacological immune suppression or genetically immune deficient mice.
-Achieving robust xenotransplantation and confirming long term safety and efficacy in animal models is an important step in determining whether human stem cell therapies can proceed to phase 1 clinical trials.
-However,the verdict is still out as to how well these xenotransplantation experiments can predict clinical success.
