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Hematotherapy and Stem Cell Research: Clinical Tools of the Future

Many diseases result from a specific defect in the immune or hematopoietic system. These diseases may be effectively treated by infusion of specific precursors of the defective cells, a process termed hematotherapy. In a typical bone marrow transplant, the entire hematopoietic system (and, consequently, the immune system) of the recipient is ablated and restored with cells from the donor. In this situation, the most primitive stem cells of the immune or hematopoietic system are eliminated and replaced. In situations such as AIDS, thrombocytopenia, certain anemias, and genetic immunodeficiency, however, only specific committed progenitor cells of the hematopoietic or immune system are affected. We may soon be able to replace these and keep the healthy portion of the patient's hematopoietic system intact.

In recent years, much interest has focused on the isolation, identification, and propagation of the stem cells of various tissues. Hematopoietic stem cells have recently been grown in culture and may soon be used for therapeutic purposes. Hematopoietic stem cells are either committed or pluripotent. As such, they either are destined to generate a specific lineage of cells or are capable of generating further developed stem cells that can commit to development along any one of several lineages. Pluripotent stem cells are needed to reconstitute hematopoiesis after the complete disruption that occurs during whole-body irradiation or after the infusion of chemotherapeutic agents to treat leukemia and solid tumors.

Committed stem cells may be used for specific defects. For example, in AIDS, virus-laden T cells are rapidly eliminated, resulting in low circulating levels. Although pharmaceutical progress has resulted in extended survival for these patients, they are at high risk for life-threatening infection resulting from low T cell levels. It may be possible to support patients by periodic infusions of T cell precursors, generated in efficient bioreactors from the patient's own primitive stem cells. These bioreactors would be fueled by specific cytokines that direct the stem cells to specifically generate committed T cell progenitors. Stem cells used to initiate the culture would be obtained from the patient's marrow and grown under virus-free conditions. After sufficient T cell progenitors were generated, the cultures would be processed to isolate and concentrate the cells. Patients would receive an infusion whenever their T cell counts plummeted, protecting them against infection and allowing sustained survival.

In addition to AIDS, hematotherapy holds promise for several other diseases and conditions as well. Infusions of neutrophil progenitors may be useful for cancer patients during aggressive therapy. Red cell progenitors may be successfully cultivated and infused for those with certain anemias. Platelet progenitors may be used in patients with one of the many forms of inborn or acquired thrombocytopenia. In addition, this emerging therapeutic approach may soon be enhanced by genetic engineering. In this process, new or modified genes are inserted into the growing stem cells to replace defective or missing ones. For example, a patient may be unable to mount an appropriate immune response because of the lack of a specific enzyme secreted by healthy leukocytes. Stem cells of these patients may be modified in culture to eliminate this defect and infused back into the patient. If the infused cells take hold and generate sufficient progeny, the patient's immune defect may be reversed, resulting in a cure of a once fatal disease.

By far, the major clinical use of stem cells to date has been to restore the hematopoietic system of patients treated with radiation or chemotherapy for cancer. Less frequently, hematopoietic stem cells have been used to augment the defective immune system of patients born with genetic defects. New uses of stem cells appear to be on the horizon. In recent years, several groups have announced the successful isolation and culture of primitive, nonhematopoietic stem cells from human embryos and fetal tissue. In addition, current reports indicate that these primitive stem cells, cells that can be induced to differentiate into any type of cell in the body, can be successfully isolated from adult tissues, including tissues that would otherwise be discarded, such as fat obtained during liposuction. Stem cells could be potentially used for the regeneration and reconstruction of all types of damaged tissues.

References

Aldhous P. Stem cells. Panacea, or Pandora's box? Nature 2000;408:897-898.

Anonymous. Stem cells. Medicine's new frontier. Mayo Clin Health Lett 2000;18:1-3.

Asahara T, Kalka C, Isner JM. Stem cell therapy and gene transfer for regeneration. Gene Ther 2000;7:451-457. Helmuth L. Neuroscience. Stem cells hear call of injured tissue. Science 2000;290:1479-1481.

Noble M. Can neural stem cells be used to track down and destroy migratory brain tumor cells while also providing a means of repairing tumor-associated damage? Proc Natl Acad Sci U S A 2000;97:12393-12395. Spangrude GJ, Cooper DD. Paradigm shifts in stem-cell biology. Semin Hemat 2000;37(1 Suppl 2):3-10.

flammatory response. They can exert potent antimicrobial effects, as well as release a variety of agents that can further amplify and perpetuate the response.

The remarkable ability of the inflammatory response to sustain itself while it generates potent cytolytic agents can result in many undesirable effects, including extensive tissue damage and pain. A variety of antiinflammatory agents control some of these undesirable effects. These agents are designed to block some of the consequences of the inflam matory response without compromising its antimicrobial efficiency. They do this by neutralizing inflammatory mediators or by preventing inflammatory cells from releasing or responding to inflammatory mediators.

Defensive Mechanisms Are Integrated Systems

As discussed above, the innate and adaptive immune systems work together in ways that obscure their differences.

Tissue injury

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