Hematopoietic Stem Cell Transplants for Severe Combined Immune Deficiency and Systemic Sclerosis

Funding Type: 
Disease Team Research I
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 
Blood stem cells, which reside in the bone marrow (BM) can generate every type of blood and immune cell. They are the only cells necessary to re-establish blood formation if the BM is wiped out by disease or by treatments such as radiation or chemotherapy, as is the case for people who undergo a BM transplant. BM transplants have been performed for >50 years as life-saving procedures for many illnesses. However, patients do not receive pure blood stem cells, and the procedure is considered high risk mainly because BM cells received from a donor contain a combination of blood stem cells plus other mature immune cells. These mature cells pose a conundrum to physicians because on the one hand, the donor’s mature cells can be beneficial to the patient by assisting blood stem cells to take root and grow in the recipient as well as potentially helping battle tumors in cancer patients. However on the other hand, these mature donor cells can attack the recipient’s tissues, perceiving them as foreign and causing a syndrome called graft-versus-host disease (GVHD). Unfortunately, 10-20% of patients that undergo a transplant die from the consequences of GVHD. In the last decade technologies were developed to purify blood stem cells eliminating mature immune cells, thereby eliminating the danger of GVHD. However, transplant physicians remained hesitant to use such grafts because of concerns that purified stem cells without the accompanying immune cells would not take and grow in the recipient. Members of this team have therefore worked out new ways in mice that may be used on patients so that they will accept purified blood stem cell grafts without significant side effects. The reagents we will develop belong to a class of proteins called antibodies. The specialized antibodies we will use are biologic tools that allow us to both purify human stem cells, and eliminate blood stem cells in the recipient thereby clearing the BM for donor cells. We plan to adapt the technologies that have worked successfully in mice to treat two different disorders for whom BM transplant can be curative, but if performed by conventional methods is very high risk and can be fatal for the patient. The disorders we aim to cure by this approach are the childhood disease called severe combined immune deficiency (SCID), and the other is an autoimmune disease called systemic sclerosis (SSc). Children born with SCID lack immune cells to fight infections and without treatment die within the first year of life. Patients with severe forms of SSc experience thickening and tightening of the skin, lung and gastrointestinal problems which ultimately results in death after several years of suffering. We intend for these studies to result in superior treatments for these diseases. Since blood stem cell transplants have the capability of curing many other childhood and autoimmune disease, the ultimate impact of our studies will potentially be on a much broader spectrum of diseases.
Statement of Benefit to California: 
In 2004 California citizens passed a historic proposition supporting research that could result in the use of stem cells to cure many diseases. As a result, public and private institutions in California have emerged as leaders in this field, and scientists are now well on the path to producing tissues from primitive embryonic stem cells (ESCs). As scientists learn to direct these cells to become the tissues needed to replace damaged or failing ones, the obstacle of a patient rejecting these new tissues is a problem that must be overcome. The studies proposed by this Team address this issue. Tissues or organs are rejected because they come from donors who are genetically different. Similarly, tissues derived from ESCs will be genetically different from patients who need these tissues and therefore at risk for rejection. In order to prevent tissue rejection, patients that undergo transplants of organs (i.e, heart, kidney, lung) must remain life-long on medications to suppress their white blood cells from rejecting the grafts. There is one group of transplant patients that are routinely taken off their immune suppressive drugs -- bone marrow transplant (BMT) patients. These patients undergo BMT to cure them of severe cancers or inherited blood diseases. However, they can be liberated from their immune suppressive drugs because donor blood forming stem cells that take root in their bodies make the white blood cells that decide which tissues are identified as “foreign” or “self”. New white blood cells re-educate the recipient’s immune system to accept donor tissues as self. Thus, a state of harmony called immune tolerance is achieved so that donor blood is made without difficulty, and, in theory, the recipient can accept transplanted organs from the marrow donor without need for immune suppression. A similar strategy can be adapted to induce immune tolerance to tissues derived from ESCs. Remarkably, BMT also has the capability to cure autoimmune diseases such as multiple sclerosis, juvenile diabetes and many others. The major obstacle to use BMT beyond the treatment cancers has been the dangers associated with the procedure. This Team will take a crucial step to make BMT safer by transplanting only purified blood stem cells. The benefits of these potential advancements to our state are many. First and foremost is the health and well-being of all Californians who face the many diseases treatable by BMT. In addition, it is a simple fact that with every major scientific advancement come immediate economic benefits to the region that generated those advancements. These benefits can manifest in the form of academic donations from sources around the world, service industries that support the medical establishments that practice the procedures, and hi tech companies who receive their funding globally. This activity can all result in greater investment in California and continued job creation that has made California such a desirable place to live.

© 2013 California Institute for Regenerative Medicine