10/11 - Transplantation

Question 1

What are the three primary roles of the immune system?

Answer 1

1. Defense against infections
2. Defense against tumors
3. Response against foreign proteins including tissue grafts

Question 2

What are major targets of tissue allograph rejection? What about for hematopoietic stem cell graphs?

Answer 2

Major histocompatibility complex (MHC) molecules, which is also referred to as the human leukocyte antigen (HLA) complex.

Hematopoietic stem cell graphs: MHC molecules or “minor” histocompatability antigens can be targets.

Question 3

Every person expresses ____ class I MHC alleeds and at least ___ class II MHC alleles. What are they?

Answer 3

6 and 6

Class I: HLA-A, HLA-B, HLA-C (one from each parent)

Class II: HLA-DR, HLA-DQ, HLADP (one from each parent)

Question 4

What are the two ways by which graft alloantigens can be presented?

Answer 4

Directly: presented to recipient T cells

Indirectly: presented by self APCs

Question 5

Which allele types of MCW have limited polymorphisms and appear to be less important in matching?

Answer 5

HLA-C and HLA-DP

C is still matched for, but DP is no longer done.

Question 6

What type of matching is important for solid organ transplants?

Answer 6

Donor and recipient MHC (HLA) proteins was important before cyclosporine and other immunosuppressants became available.

Now HLA matching is not considered necessary for many types of organ transplants (but is still widely used for kidney transplanting).

Question 7

What type of matching is important for hematopoietic stem cell transplants?

Answer 7

Some genetic disparity can be overcome with immune suppression, MHC matching is still important.

Question 8

What is direct alloantigen recognition?

Answer 8

T cell recognizes allogenic (foreign) MHC on graft APC.

Foregin MHC looks enough like self that T cells crossreact and bind TIGHTLY.

Up to 10% of T cells can react, causing inflammation.

Question 9

What is indirect alloantigen recognition?

Answer 9

Allogenic MHC from the donor cell is chewed it up into peptides which are then bound to self MHC and presented by an APC to self T cell.

(Normal antigen presentation process-same thing that would happen if there was a microbe).

Question 10

What is autologous? What is allogenic? What is xenogeneic?

Answer 10

Autologous: self-transplant

Allogenic: Transplant from another person

Xenogeneic: Across species

Question 11

What is chimerism?

Answer 11

Mixture of donor and host

Question 12

What are the three types of rejection? How common is each and when does each happen temporally?

Answer 12

1. Hyperacute: immediate rejection, rare now due to screening
2. Acute: cellular or humoral rejection occus within days to weeks in non-immunosuppressed pts or months to years in immunosuppressed pts. (usually wont occur because people remain immunosuppressed)
3. Chronic: major problem now; occurs in months to years. Caused by tissue damage such as scarring and fibrosis that ultimately causes loss of graft.

Question 13

How is graft rejection prevented? What are negative effects of this prevention method?

Answer 13

Immune suppressive drugs; mainstay is cyclosporine.

Side effects: increased risk of infection or cancer

Question 14

How long do patients need to stay on immunosuppressive drugs?

Answer 14

Solid organ transplants: usually lifelong

Stem cell transplants: usually weened off (or at least that’s the goal)

Question 15

What is hematopoietic stem cell transplantation (HSCT) used for? How are they obtained?

Answer 15

Therapy for hematopoietuc and non-hematopoietic malignancies, aplastic anemia, and immune deficiencies.

Historically from BM, now from peripheral blood (after mobilization by growth factors or chemokine receptor inhibitors) or umbilical cord blood.

Question 16

What does a recipient need to do before receicing a hematopoietic stem cell transplant?

Answer 16

Recipient (autologous (self) or allogenic (nonself)) treated with chemo and/or irradiation to eliminate malignant/diseased cells.

• This allows space for incoming HSCs which can then move into the BM.

Question 17

What is a haploidentical donor for HSCT?

Answer 17

An allogenic donor with half of same typing as the recipient (a parent)

Question 18

What are some immune problems associated with allogenic hematopoietic stem cells?

Answer 18

• finding a donor (histocompatability)
• graft-vs-host disease (acute & chronic)
• infection (immune deficiency
• graft rejection
• malignant disease relapse
• slow immune recovery

Question 19

What are the four stages of graft-vs-host disease defined by?

Answer 19

There are four classifications, one being the lest severe and four being the most severe.

The major targets of GVHD are skin, liver, and GI tract. The stagging of GVHD is based on the magnitude of effects in these tissues.

Question 20

What is a mixed lymphocyte reaction?

Answer 20

When you mix cells from one person with cells from another.

The cells from one person are inactivated; this models alloreactivity and may predict GVHD.

Useful when looking at MHC differences.

Question 21

For both types of transplants (solid organ and hematopoietic SC), ________ cell responses occur due to alloantigen differences between the donor and recipient.

Answer 21

T and B cell responses

Question 22

In hematopoietic stem cell transplantation, the immune reactivity is _________? What is the biggest problem and what causes it?

Answer 22

Bidirectional: donor anti recipient (GVHD) and recipient anti donor (rejection) can occur.

GVHD is the biggest problem, and it’s driven by donor T cells.

Question 23

In solid organ transplant, the immune reactivity is __________. What is this driven by?

Answer 23

Mainly unidirectional: recipient anti donor (rejection).

Acute rejection os mainly driven by recipient T cells and can involve B cells (Ab)

Chronic rejection can involve DC4+ cells and B cells

Question 24

In HSCT what plays an important role in alloreactivity? What about for solid organ transplant?

Answer 24

HSCT: both major and minor histocompatability antigens (HAs)

Solid organ: major HA reactivity drives rejection (role of minor not as important)

Question 25

The success of both solid organ transplantation and HSCT is dependent on what?

Answer 25

The use of immunosuppressive drugs.

Question 26

What are the basic components of HPSC transplantation?

Answer 26

1. Condition

• immunosuppressants
• eradicate the disease
• Non-myeloablative (less aggressove, less damage than the older myoablative)

2. HPSC infuctoin
   * GHVD prevention strategies
3. Deal with it (complications)

Question 27

What is it called when the host attacks the donor?

Answer 27

Graft rejection :(

Question 28

What is it called when the donor attacks the host?

Answer 28

Graft vs host disease :(

Question 29

What is it called when donor (graft) T cells attack leukemia?

Answer 29

Graft vs. leukemia (GVL) :)

Question 30

In order to have GVHD one must have what three things?

Answer 30

1. Immune compromised host
2. Immune competent graft
3. HistoINcompatibility

Question 31

How does BMT rejection show itself clinically? What do you want in the first three weeks post-transplant (ie in the blood)?

Answer 31

Rejection: white count goes up and then down. Lymphocytes go up (T cells)

Ideally: high PMN and low lymphocytes

Question 32

What is graft vs leukemia (GVL)?

Answer 32

Alloreactivity fighting off leukemia (good thing!)

Patients with graft vs host disease had a lower risk of relapse post-BMT: this is because if the graft is attacking self (bad), it will also attack the leukemia and cause graft vs leukemia (good)

Question 33

If someone has true SCID, do you need to irradiate the patient before transplantation? What does irradiation do?

Answer 33

Nope, in true SCID the patient has no B and T cells so they have nothing that could react to the transplant.

Irradiation prevents any immune cells from ever dividing again.