Pass The Specificity, Please:
Allotransplantation in the New Millenium

By Martin L. Carroll, M.D.

For two decades, a major goal of bone marrow transplanters treating acute leukemia has been to deliver the therapeutic benefit of an allogeneic bone marrow transplant while minimizing the toxic effects. One of the major toxicities of an allogeneic BMT is graft versus host disease, a severe and potentially life threatening complication of having one’s bodily house reconstituted with a new immune system. Early on it was clear that T-cells transferred with the bone marrow donation conveyed the immunologic message leading to GVHD and experiments were done to test the effects of T-cell depleted bone marrow donations. As predicted, the incidence of GVHD was decreased; however, overall survival did not improve because there is a concomitant decrease in graft vs. leukemia (GVL) effect leading to an increase in leukemia relapse. Ongoing efforts to solve this dilemma by identifying the distinct immunologic variables distinguishing GVH response from GVL response were discussed in the Education Program session, New Developments in Allotransplant Immunology, chaired by

Dr. A. John Barrett. Dr. Barrett reviewed new advances in understanding the role of T-cells and T-cell activation after transplantation in mediating GVHD and GVL. Recent findings have indicated that donor T-cells that mediate GVHD are initially activated by antigen presenting cells (APCs) within the host in an HLA matched transplant. In other words, the initiating cell for GVHD is the donor’s own APCs or dendritic cells (DCs). If this is true, then elimination of the radiation and chemotherapy resistant dendritic cells by specific therapies directed against DCs may decrease or eliminate GVHD. This hypothesis is being tested experimentally and may lead to new trials in the future.

It has long been known that GVHD is driven in part by a so-called “cytokine storm” occurring within host tissues. Preparative regimens cause tissue damage that leads to release of a large number of inflammatory cytokines including IL1, IL6, IL10, interferons, and TNF. Dr. Anne Dickinson presented interesting new results that may explain why some patients develop severe GVHD but others develop only mild GVHD. Data from the human genome project has led to the recognition that there is significant variability within the DNA sequence for the regulatory regions of genes including the cytokine genes. These variations or polymorphisms have been found to lead to alterations in the amount of cytokine produced in response to stimuli. Thus, within the population, there are high and low cytokine secretors. Dr. Dickinson reviewed recent reports that the incidence of severe GVHD correlates in several cases with being a high cytokine secretor of pro-inflammatory cytokines such as TNF alpha or being a low secretor of IL10, a TNF alpha antagonist. Compelling data associating the incidence of GVHD with single polymorphisms was reviewed, but Dr. Dickinson warned that most studies have not incorporated a multi-variate analysis allowing for definition of the critical regulators. Large studies using uniform preparative regimens, uniform methodologies for HLA matching and following multiple polymorphisms will be necessary to determine the role of these apparently random mutations in gene sequence in determining one’s risk for GVHD.

Finally, Dr. Nelson Chao turned his attention again to those pesky T-cells. Dr. Chao reviewed recent work that has led to the splitting of T-cells into different functional groups. Both CD4+ helper cells and CD8+ cytotoxic cells can be subdivided into, respectively, Th1 and Th2 or Tc1 and Tc2 populations. The critical observation is that Th2 cells do not mediate GVHD and Tc2 cells do mediate GVL effects. Thus, depletion specifically of Th1 and Tc1 cells from the donor marrow may minimize GVHD and still allow for the development of GVL. A clinical trial testing this hypothesis has recently been initiated.

A full review of the complex immunology involved in allo-transplantation is beyond this space; however, it is clear that an improved understanding of the specifics of the alloimmune response is raising new possibilities for modifying this response therapeutically. Furthermore, the technology is available to purify the requisite subsets of cells involved, to expand them ex vivo, and to follow those cells over time in the transplant recipient. I would anticipate that the confluence of these factors will generate its own “perfect storm” that will allow for much more sophisticated applications of bone marrow transplantation in the near future.