Chapter 5: Rejection of Transplants

Question 1

What is the foundation on why transplants can be rejected?

Answer 1

The differences in HLA alleles.

Question 2

What are allografts?

Answer 2

Grafts exchanged between individuals of the same species

Question 3

The recipient’s T cells recognize donor antigens from the graft (the allogeneic
antigens, or alloantigens) by two pathways. What are these two pathways?

Answer 3

These two pathways are the direct and indirect pathway of recognition of alloantigens. The graft antigens are presented directly to recipient T cells by graft APCs. Or the graft antigens are picked up by host APCs and presented to host T cells (indirect).

Question 4

What do both pathways lead to after presenting the graft antigen to APC?

Answer 4

They both lead to the activation of CD8+ T cells and CD4+ T cells. They respectively develop into CTLs and mainly Th1 cells.

Question 5

Why are immune respones to allografts stronger than responses to pathogens?

Answer 5

The frequence of T cells that can recognize the foreign antigens in a graft is much higer than the frequency of T cells specific for any microbe.

Question 6

Just read

Answer 6

Graft rejection is classified into hyperacute, acute, and chronic, on the basis of clinical and pathologic features. This classification was devised by nephrologists and pathologists based on rejection of kidney allografts, and has stood the test of time remarkably well. Each type of rejection is mediated by a particular kind of immune response

Question 7

How is the hyperacute rejection mediated?

Answer 7

This type of rejection is mediated through binding of antibodies to antigens on the graft endothelium. This activates the complement and clotting systems, leiding to endothelial injury, thrombus formation and ischemic necrosis of the graft.

Question 8

What type of preformed antibodies are there during a hyperacute rejection?

Answer 8

IgM specific for blood group antigens or antibodies specific for allogeneic MH moleculesthat
were induced by prior exposure through blood transfusions, pregnancy, or organ transplantation

Question 9

Why is a hyperacute rejection not so common?

Answer 9

Because every donor and recipient are matched for blood type and potential recipients are tested for antibodies against the cells of the prospective donor (cross-matching).

Question 10

Acute rejection is divided into acute cellular rejection and acute antibody-mediated (vascular or humoral) rejection. What is the difference?

Answer 10

In acute cellular rejection CD8+ CTLs may directly destroy graft cells or CD4+ cells secrete cytokines that induce inflammation, which damages the graft. T cells also may react against graft vessels,
leading to vascular damage.
In acute antibody-mediated rejection antibodies bind to vascular endothelium and activate complement via the classical pathway. This results in inflammation and endothelial damage.

Question 11

When does acute rejection occur?

Answer 11

Within days or weeks after transplantation and is the
principal cause of early graft failure. It also may appear suddenly months or even years later, after immunosuppression is tapered or terminated.

Question 12

What two things happens during chronic rejection?

Answer 12

Interstitial fibrosis occurs and gradual narrowing of the graft blood vessels occurs (graft arteriosclerosis).

Question 13

What is the cause of interstitial fibrosis and graft arteriosclerosis?

Answer 13

T cells that react against graft alloantigens and secrete cytokines which stimulate the proliferation and activities of fibroblasts and vasculare smooth muscle cells.

Question 14

What is a isograft or syngeneic graft?

Answer 14

A graft that is donated by an identical twin and received by the other identical twin.

Question 15

What is a xenograft?

Answer 15

A graft of a donor that is a different species than the recipient.

Question 16

What is an autograft?

Answer 16

A graft from the same individual that will receive the graft.

Question 17

Immunnosuppression of the recipient is a necessity in all organ transplantations. Are there exceptions?

Answer 17

Yes, the exception applies for auto- and isografts.

Question 18

What is a downside of immunosuppression during organ transplantations?

Answer 18

Suppression of the immune system results in increased susceptibility to fingal, viral and other infections. Its even possible that latent viruses can get reactivated (like cytomegalovirus and polyoma virus). Patients also have a higer risk of developing virus-induced tumors (such as epistein-barr virus or HPV).

Question 19

How do we bypass the negative effects of immune suppression?

Answer 19

By inducing donor-specific tolerance in host T cells.

Question 20

How do we induce donor-specific tolerance in host T cells?

Answer 20

One way is by preventing host T cells from receiving costimulatory signals form donor DCs during the initial phase of sensitization. This can be done by an agent that blocks the interaction of B7 molecules (on DCs) and the CD28 receptor (on T cells).

Question 21

Can hematopoietic stem cells be used in any disease?

Answer 21

No, it’s a dangerous procedure and therefore only used in life-threatening conditions.

Question 22

Are hematopoietic stem cells only derived from the bone marrow or can they be derived from anywhere else?

Answer 22

Hematopoietic stem cells are obtained from the bone marrow, but now also usually harvested from peripheral bloodafter they are mobilized from the bone marrow by administration of hematopoietic growth factors, or from the
umbilical cord blood of newborn infants, a rich source of
HSCs.

Question 23

What must be done before transplantation of hematopoietic stem cells?

Answer 23

The recipient’s immune system is destroyed so that it ‘opens up’ places where hematopoietic stem cells are nurtured. This makes sure the transplanted stem cells can be engrafted.

Question 24

What two major complications can arise during hematopoietic stem cell transplantation?

Answer 24

Graft-versus-host disease and immune deficiency.

Question 25

What is graft-versus-host disease?

Answer 25

It occurs when allogeneic hematopoietic stem cells are transplanted. Here the host cannot reject the graft (because their immune system is destroyed), but T cells present in the donor graft perceive the host’s tissue as foreign and react against it. This results in the activation of donor CD4+ and CD8+ T cells, causing inflammation and killing of recipient cells.

Question 26

How is the risk of graft-versus-host disease minimized?

Answer 26

Hematopoietic stem cell transplants are done between donor and recipient that are carefully HLA-matched.

Question 27

There are two forms of graft-versus-host disease (GVHD): acute GVHD and chronic GVHD. What happens during acute GVHD?

Answer 27

This type occurs days to weeks after transplantation, where it causes epithelial cell necrosis in the liver, skin and gut. This results in jaundice (as a result of bile duct destruction), bloody diarrhea (mucosal ulceration of the gut) and rash.

Question 28

There are two forms of graft-versus-host disease (GVHD): acute GVHD and chronic GVHD. What happens during chronic GVHD?

Answer 28

This type may follow the acute syndrome, but not necessarily. Patients develop skin lesions resembling those of systemic sclerosis and
manifestations mimicking other autoimmune disorders.

Question 29

Because GVHD is mediated by T lymphocytes contained in the transplanted donor cells, depletion of donor T cells before transplantation virtually eliminates the
disease Why is this now always a good idea?

Answer 29

Because the recurrence of tumor in leukemic patients as well as the incidence of graft
failures and EBV-related B-cell lymphoma increase.