Embryonic kidneyLast week I talked about regulatory T cells (TRegs) in cancer. TRegs are often abundant in tumors, and have been linked to poor outcome, presumably because they prevent immune rejection of the tumor. The obvious flip side of this would be in a situation where you want to prevent immune rejection — in organ transplants. TRegs have been frustratingly hard to harness for this, though. (“Tolerance is the future of transplantation, and always will be.” –Norman Shumway)

A paper in the New England Journal of Medicine1 describes an encouraging step forward in this, achieving something that is at least close to the holy grail of transplantation — organ transplants that are maintained indefinitely without immunosuppression. Normally, organ transplants are rejected by the immune system, unless they’re from an identical twin (in which case the donor organ is perceived to be “self” by the immune system). By suppressing immunity, organ transplants can “take” without rejection; usually the immunosuppression is fairly harsh at first, but can be eased up over time, suggesting that a certain degree of tolerance is reached. (Also, the donor organ probably becomes less immunogenic over time, as some of the most immunogenic cells move out of the graft or die off, leaving less immunogenic tissues behind.)

Even though today’s immunosuppression is relatively gentle and focused, it’s only gentle relative to previous brutal treatments; it still leaves the recipient susceptible to infection, so there’s always a juggling act, balancing risk of rejection with risk of infection. The goal, then, has long been to find techniques that will allow the recipient’s immune system to become tolerant of the donor organ, as is seen in tumors.

Embryonic kidneyThe paper describes five kidney transplants that were preceded by bone marrow transfer from the donor. In four of the five cases, they were able to withdraw immunosuppression altogether, and the transplant wasn’t rejected (for at least one to five years, and counting). This is particularly exciting because these transplants weren’t from HLA-matched donors, meaning they were fairly immunogenic. (The same group, and another paper in the same issue of New England Journal, have done the same thing with HLA-matched transplants,2 which is still pretty interesting; but partially-mismatched transplants are much more common these days. )

One particularly interesting observation is that the bone marrow transfer only led to temporary chimerism (i.e. the donor bone marrow didn’t take permanently, and after a while only the original recipient bone marrow cells were present); but the tolerance persisted. They were able to find lots of TRegs infiltrating the donor kidneys, though, and so they believe that the long-term tolerance is probably because of TRegs (peripheral tolerance) although in the early stages thymic effects (central tolerance) may have been more important.

Blogging on Peer-Reviewed ResearchThe same issue of New England Journal describes the case of a young liver transplant recipient who apparently had her bone marrow seeded with stem cells from the donor liver, resulting in a switch of blood type and immune system to the donor’s and, again, a complete take of the graft without immunosuppression.3 That’s the case that’s getting all kinds of press right now, but while it may turn out to be an important guide to future treatment, it was essentially pure luck — the other cases here were the result of deliberate planning and defined conditions, which means that they can be repeated; the flashy case can’t, yet.

  1. Kawai, T. et al., 2008. HLA-Mismatched Renal Transplantation without Maintenance Immunosuppression. N Engl J Med, 358(4), p.353-361. []
  2. Bühler, L.H. et al., 2002. Induction of kidney allograft tolerance after transient lymphohematopoietic chimerism in patients with multiple myeloma and end-stage renal disease. Transplantation, 74(10), p.1405-9.
    Fudaba, Y. et al., 2006. Myeloma responses and tolerance following combined kidney and nonmyeloablative marrow transplantation: in vivo and in vitro analyses. American journal of transplantation, 6(9), p.2121-33.
    Spitzer, T.R. et al., 1999. Combined histocompatibility leukocyte antigen-matched donor bone marrow and renal transplantation for multiple myeloma with end stage renal disease: the induction of allograft tolerance through mixed lymphohematopoietic chimerism. Transplantation, 68(4), p.480-4.
    Scandling, J.D. et al., 2008.
    Tolerance and Chimerism after Renal and Hematopoietic-Cell Transplantation. N Engl J Med, 358(4), p.362-368. []
  3. Alexander, S.I. et al., 2008. Chimerism and Tolerance in a Recipient of a Deceased-Donor Liver Transplant. N Engl J Med, 358(4), p.369-374. []