Sickle cell disease is an inherited blood disorder in which cells containing hemoglobin (a protein in red blood cells that carries oxygen to the tissues of the body) form in the shape of a sickle, or crescent, instead of a disc scape. These sickle cells tend to cluster together, and cannot easily move through the blood vessels. The cluster can cause blockages in small arteries or capillaries, stopping the movement of healthy, normal oxygen-carrying blood. These blockages can cause painful, damaging complications.

The disease causes lifelong, chronic injury to the body tissues, including the bones, kidneys, and eyes. Learn more about Sickle Cell Disease.

While some of the side effects of sickle cell disease can be managed with medications or blood transfusions from healthy donors, the only known cure is a bone marrow or stem cell transplant.

Using a novel bone marrow transplant treatment plan developed at Johns Hopkins, physicians at the Johns Hopkins Kimmel Cancer Center and the Johns Hopkins Children’s Center have cured some children with sickle cell disease.

Normally, for children with the disease to have a successful transplant, they need a donor who matches their tissue type, specifically their human leukocyte antigen (HLA) tissue type. HLAs are proteins found on most cells in the body; the immune system uses these markers to recognize cells that belong in the body versus those that do not. The closer the match between a patient’s HLA markers and the donor’s, the better for the patient. The best “full” matches are brothers or  sisters, but this has been difficult in sickle cell patients because some of the patients’ siblings also may have sickle cell disease or carry the gene. Only about 25 percent of children with the disease have relatives that match well enough to receive a transplant.

But in a treatment developed here at Johns Hopkins, children need just a “half-match” for a successful transplant, meaning that a patient’s parents could be suitable donors. This dramatically increases the number of patients who can successfully be transplanted.

First, doctors give patients medication to suppress their immune system, which keeps patients from rejecting the donor cells. Then, three days after the transplant, patients are given a high dose of a drug called cyclophosphamide to “re-boot” the immune system. The procedure is very safe and has a low risk of graft-versus-host disease, a complication in which the body attacks the donated cells.

Read more about Haploidentical Transplantation and the Pediatric Bone Marrow Transplant Program.

Research

Physicians with the Sickle Cell Transplant program, including Allen Chen, associate professor of oncology and pediatrics, and Christopher Gamper, assistant professor of oncology, continue to study the immune system and the transplant process.

Dr. Gamper’s research seeks to identify factors critical to regulation of T cell effector function and memory. T cells are an essential component of the adaptive immune response that specialize after activation to more efficiently target and destroy not only infected tissues but also tumor cells. Tumors are capable, however, of misdirecting the specialization of T cells and rendering them unresponsive. One mechanism that appears to contribute to this unresponsiveness is the permanent silencing of genes, including immune hormones called cytokines, by DNA methylation. Experiments designed to identify genes whose expression is increased in unresponsive T cells demonstrated that DNA Methyltransferase 3a (DNMT3a), which catalyzes addition of new methylation to DNA, is highly expressed in unresponsive cells. Dr. Gamper generated mice that have T cells lacking DNMT3a and found that such T cells can specialize normally following activation but unlike normal T cells, DNMT3a deficient T cells can be reprogrammed to secrete cytokines that are normally silenced because they fail to methylate the DNA of these cytokine genes. These findings suggest that use of drugs that block DNA methylation may be helpful to reawaken desirable anti-tumor cytokine gene expression and enhance cancer vaccine strategies. Dr. Gamper is working with a colleague, Dr. Brian Ladle, to translate these findings into improved cancer immunotherapy.

Dr. Gamper’s clinical specialty is bone marrow transplant. Bone marrow transplantation is another area where understanding the factors that promote and inhibit immune activation can have immediate clinical application. Following transplant, an intense graft versus tumor (GVT) response can help to destroy cancer cells that remain after prior chemotherapy or radiation, but it is often accompanied by immune attack against normal host tissues, termed graft versus host disease (GVHD). Steroids are the primary treatment for GVHD, but up to 40% of patients do not respond to steroids, which can result in death from organ injury or opportunistic infections. Dr. Gamper is also working to open clinical trials to identify novel agents for the treatment of acute GVHD that fails to respond to steroids. Additionally, some patients require a bone marrow transplant for non-cancerous conditions such as sickle cell anemia. Such patients do not require the anti-cancer benefit of high dose chemotherapy, and GVHD can only cause them serious side effects. Efforts are underway to develop safer reduced intensity transplant protocols for such patients using half-matched parents or siblings as donors, based on the safety and success of such an approach in recent clinical trials at Johns Hopkins for patients with leukemia or lymphoma. Currently Dr. Gamper is working with his medical oncology colleague Dr. Javier Bolanos-Meade to perform reduced intensity BMT using half-matched parent or sibling donors to treat sickle cell anemia using a technique employing post-transplantation cyclophosphamide. By using such half-matched donors who are permitted to have sickle cell trait, bone marrow transplantation to cure sickle cell anemia could become much more widely available than relying on fully matched sibling donors. Early results from this trial are promising and were published in the journal Blood.