Radiation Induced Bacterial Translocation Causes GVHD

Tuesday March 10th, 2009 @ 02:44:56 EST

From Category: Immunology

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When cord blood stem cells are used in the context of treatment of leukemia, graft versus host has been reported to occur in some patients. Although incidence is reduced in patients who receive hematopoietic stem cells in the form of cord blood as compared to bone marrow, GVHD is still a concern. An important question is why this does not seem to occur in patients receiving cord blood for regenerative conditions such as post infarct or for liver failure?

Before we go on, we need to ask the question: So how do we know that in general cord blood does not induce graft versus host when transplanted into an immune competent host? There are three lines of reasoning. The first is that cord blood has been used in WWII as a substitute for blood transfusions, with no adverse reactions reported. The second comes from publications describing the current day use of cord blood in India and Africa for a numerous conditions such as advanced cancer, and HIV, without reports of GVHD. Perhaps most stunning are examples of mother's receiving infusions of paternal lymphocytes without detection of GVHD.

So why is there GVHD associated with leukemia treatment but not with transfusion of cord blood into immune competent hosts? Part of the answer seems to be associated with the fact that in leukemias, for the transplant to be successful, quite a large amount of recipient immune depletion needs to occur. This causes what is known as an "empty compartment".

Under normal conditions there is a balance between cytokines generated by the stroma, such as IL-7 and IL-15, and cytokines being "consumed" by the T cells and NK cells. Essentially, the T cells and NK cells act as "cytokine sinks" absorbing circulating cytokines at a similar rate to which they are generated. Under these normal conditions for a T cell to be activated it has to receive a signal through the T cell receptor, and also a signal through costimulatory molecules such as CD80, or CD86.

When there is depletion of lymphocytes, there is a higher concentration of IL-7 and IL-15 that is detected since the "cytokine sinks" are no longer there to absorb the cytokines. These high circulating levels of IL-7 and IL-15 then are able to "supercharge" the T cell so that it no longer needs a high degree of T cell receptor signaling, and requirement for costimulation is reduce. This causes the situation in which T cells can start reacting to antigens that they would normally not react with.

This concept that "left over" or exogenously administered (eg lymphocyte contamination in a stem cell graft) T cells to host that is lymphodepleted can result in exaggerated immunity has been demonstrated in three main settings:

a) it is difficult to induce transplant tolerance following lymphodepletion
b) autoimmunity is augmented by lymphodepletion (eg accelerated diabetes in NOD after cyclophosphamide)
c) easier to induce cancer immunity in mice and man after lymphodepletion

An interesting paper (Paulos et al. Clin Invest. 2007 Aug;117(8):2197-204) proposes another alternative to the "cytokine sink" concept for explaining how lymphodepletion results in potentially autoreactive immunity.

The authors demonstrated that administration of tumor-reactive into mice lacking T B and NK cells would lead to inhibition of melanoma growth, but inhibition was profoundly increased if the mice were pre-treated with radiation. The interesting point was that if the effect of the radiation was solely based on induction of lymphopenia, then there should not have been any therapeutic effect since the animals had no lymphocytes to begin with !

So the authors then examined the gut of the mice and demonstrated morphological alterations indicative of injury, as well as increased endotoxin and inflammatory cytokines in the plasma. Even more interestingly, there was an influx of dendritic cells into the spleen and lymph nodes.

To demonstrate conclusively that radiation-induced translocation of the bacteria or components thereof were responsible for the immune modulatory effect, the investigators pretreated the animals with antibiotic (Cipro). Antibiotic pretreatment reduced radiation-induced plasma endotoxin and inflammatory cytokines, and also abrogated tumor immunity.

This paper has profound implications. For example, pre-transplant manipulation of the gut microflora may be a useful way of addressing GVHD. Additionally, in cancer immunotherapy there may be a role of agents that induce a temporary permeabilization of the gut. It should be noted that mesenchymal stem cells can actually inhibit homeostatic proliferation.

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