How does Graft-versus-host disease work?

[BlondeCookie]

What I know about GVHD (Graft-versus-host Disease) is this...
- bone marrow transplant to recipient
- the donor's bone marrow contains mature T lymphocytes that attack cells of the recipient
- thus the name, Graft-versus-host disease

So, in order to have an immune response, the mature T-cells from the donor recognize the recipient cells as foreign, and an immune reaction ensues. My question is, if bone marrow is being transplanted, wouldn't there be immature T-cells transplanted from the donor instead of mature T-cells? If immature T-cells are transplanted, there would be no immune reaction and thus, no such thing as Graft-versus-host Disease. Obviously, this isn't the case.

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[Strength&Speed]

First of all, I'm curious why you are asking such a detailed question which won't likely be asked on Step 1. There will be enough mature T cells in bone marrow graft to attack the host. That's all you really need to know. I can't say for sure if the immature T's can mature in the host, but there will be enough mature T's to cause a problem.

 

[Pinkertinkle]

Something about the thymus being where T cells mature and not bone marrow.

 

[MSKalltheway]

I could have sworn I read somewhere that later in life after childhood, patients receiving a thymectomy were still able to produce mature T cells, so the thymus is not the only place mature T's come from...I dont think they are entirely sure where the mature T cells come from other than the thymus. Dont quote me on that though.

 

[BlondeCookie]

First of all, I'm curious why you are asking such a detailed question which won't likely be asked on Step 1. There will be enough mature T cells in bone marrow graft to attack the host. That's all you really need to know. I can't say for sure if the immature T's can mature in the host, but there will be enough mature T's to cause a problem.

From what I have learned in my Immuno studies, the bone marrow has stem cells, some of which develop into immature T-cells that travel to the thymus and become mature T-cells. Only mature T-cells have any functionality in the immune system. Thus, if we assume that bone marrow is transplanted to a recipient, then we also assume that immature T-cells are transplanted as well. So, how can we have Graft-versus-host Disease if those T-cells are immature and non-functional?

Sorry for the minutiae in the post. I just want to figure this out for one of my practice questions. I'm sure my line of reasoning is flawed somewhere, but I just don't know quite where.

 

[synapse lapse]

I think we were taught along the lines of that mentioned above, that there are a number of mature T cells present in the graft BM that attack the host as "foreign" tissue, but Immuno was a long time ago and I don't feel like looking more into it right now.

 

[Strength&Speed]

From what I have learned in my Immuno studies, the bone marrow has stem cells, some of which develop into immature T-cells that travel to the thymus and become mature T-cells. Only mature T-cells have any functionality in the immune system. Thus, if we assume that bone marrow is transplanted to a recipient, then we also assume that immature T-cells are transplanted as well. So, how can we have Graft-versus-host Disease if those T-cells are immature and non-functional?

Sorry for the minutiae in the post. I just want to figure this out for one of my practice questions. I'm sure my line of reasoning is flawed somewhere, but I just don't know quite where.

I think the answer to your question is that there are mature as well as immature T-cells in the bone marrow. Its not 100% of one, 0% of the other.

This is not the best source, but I'll copy an article:
Hale, S Bright, G Chumbley, T Hoang, D Metcalf, AJ Munro and H Waldmann


Graft-versus-host disease is one of the major problems in clinical bone marrow transplantation. Many experiments in animals have shown that it could be greatly reduced if mature T lymphocytes were removed from the donor marrow. Here we describe a new rat monoclonal antibody, CAMPATH 1, which is suitable for depleting lymphocytes from human marrow grafts. CAMPATH 1 is an IgM that fixes human complement. It binds to both T and B lymphocytes and some monocytes but not to other hemopoietic cells. When peripheral blood mononuclear cells were treated with CAMPATH 1 and complement, more than 99% of lymphocytes were killed and viable T cells could no longer be detected. Under these conditions, in vitro multipotential erythroid and myeloid colony-forming cells were unaffected. As well as being used for in vitro treatment of bone marrow to remove T cells, CAMPATH 1 could potentially be applied to other experimental and clinical situations where depletion of lymphoid cells is required, including serotherapy to achieve immunosuppression for organ transplants or to treat lymphocytic leukemias.

 

[medsurg2010]

Not sure if you are looking for step 1 specific info, but I did have a Kaplan qbank question that incorrectly stated that gvhd was NK-cell mediated (I answered T cell, which was incorrect). I wrote kaplan an email marking this as an error in their qbank.

In fact, infusions of autologous NK cells with a BMT has been shown to decrease the incidence of GVHD and increase the preferable anti-tumor response. The questions you should be able to answer as far as step 1 is concerned (IMHO) are:

1. MHC restriction and GVHD. Answer the question of: Why donor T cells become effector cells in an acute GVHD model if they are MHC-restricted?

2. What are the minor and major antigens? Why is there still an allogeneic response in an identical twin bone marrow transplant-- minor antigens.

3. What are the major cytokines involved in Th1 and Th2 reactions? What are the signals for activation of T cells?

4. What are the 3 stages of acute gvhd and describe the cytokines in each.

5. Know a clinical vignette of gvhd (symptoms and signs) and the time frame for hyperacute, acute, chronic rejection.

Usually, grafts are T-cell depleted, but this may be a catch-22. Depleting T cells may not be entirely beneficial because the CD4+CD25+ foxp3+ T regulatory cells ("T regs") have been shown to prevent acute gvhd. FWIW, you should focus on the thymus serving as an organ to develop self-tolerance, not necessarily T cell maturation. In which case, it would make sense that tolerance would not be generated in an adult with an involuted thymus who receives a transplant of "immature T cells." Graft T cell maturation and expansion in the recipient is more dependent upon inflammatory cytokine production (thought to be caused by the chemo and/or radiation prior to the transplant). The activated T cells produce IL-2, which begins the "effector" phase, where clinical manifestations occur due to cytotoxic T cell damage to host tissue, thought to be initiated by graft T cell/ host antigen presenting cell interaction.

This is a review that I found especially helpful (I was enslaved, er... I mean employed in a gvhd research lab in undergrad).

Hope that helped. PM me with any questions.

CITATION:
Acute graft-versus-host disease: Pathophysiology, clinical manifestations, and management
Daniel Couriel, M.D.*, Humberto Caldera, M.D., Richard Champlin, M.D., Krishna Komanduri, M.D.
Department of Blood and Marrow Transplantation, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
email: Daniel Couriel ([email protected])

*Correspondence to Daniel Couriel, Department of Blood and Marrow Transplantation, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 423, Houston, TX 77030-4009