Seattle Treatment Education Project (STEP) Perspective, Vol. 5, No. 2 -

Since the beginning of the AIDS pandemic, great attention has been paid to the role of CD4 lymphocytes. This is because HIV primarily infects this subset of lymphocytes, although other cell types can also become infected. Also, decreases in CD4 cells somewhat parallel clinical progression of HIV disease. What has not received nearly as much attention or scrutiny is the role, activity, and sheer number of CD8 cells. There have been a few lone voices in this area in the last few years which have concentrated on this latter subset of lymphocytes. This article will review the role of CD8 cells in the suppression of HIV, their anti-tumor activity, as well as their role in the development of opportunistic infections (OIs) in advanced-stage disease. CD8 cells play an important role in the immune response. They have at least three major roles. One is to turn off any particular immune response after that response has been generated by the CD4 cells. This is known as the "suppressor" function of CD8 cells and why the older term for them was "T suppressor cells." This function serves as an effective check on the immune response and on the activity of CD4 stimulation on that response. However, an equally important function of CD8 cells is their ability to kill virally-infected cells. This function, aided by the presence of antibody to the virus, allows the CD8 cells to determine which cells are infected by a virus, and then enables the destruction of these infected cells. This is known as CD8's "cytotoxic" function and hence cells responsible are known as "Tcyt." In addition to these two functions of CD8 cells, it is known that they also are responsible for secreting various chemicals called cytokines which have effects on other cells 3. These effects can be quite varied and range from cell stimulation, growth, and multiplication to cell inactivation and death. Also, cells which possess the CD8 marker function to limit the growth of tumor cells 1,2,7. Individuals early in their infection with HIV have increased numbers of CD8 cells. Normal levels of this lymphocyte subset in uninfected people are around 300-800/ul. However, in HIV infection, numbers higher than this are not uncommon. Even as the number of CD4 cells dips below 200, high numbers of CD8 cells are looked upon favorably. This is because of their role in the control of HIV infection by the mechanisms previously mentioned. In a study looking at the development of OIs in late stage disease, the incidence of disseminated CMV and MAI increased when CD8 cells fell below 500/ul 4. All of the patients had CD4 counts of less than 50, but it was not until their mean CD8 cell count dropped below 500 that these two OIs were seen with increasing frequency. Since CD8 cells have this beneficial effect in HIV infection, it is natural to wonder if their numbers could somehow be increased. One possibility would be to infuse CD8 cells -which were donated by one or several people - into an HIV infected person. But in studies where this was done in vitro, control of HIV infection did not occur or did not occur to the same magnitude as when one's own CD8 cells were put in with their own infected peripheral blood mononuclear cells (PBMCs) 3,5. The other possibility is to expand one's own population of CD8 cells outside the body and then reinfuse them. This is what was initially attempted in 1990-1991 in two small phase I studies which were reported on at the VII International AIDS Conference in Florence 6. Briefly, six patients from the Univeristy of Pittsburgh and six patients from the University of Miami with CD4 cells between 10 and 650 had their CD8 cells separated from the rest of their PBMCs. These CD8 cells were then expanded by a methodology developed by Applied Immunosciences and infused back into the corresponding patient. This procedure was performed multiple times with two to three weeks of "rest" in between. Since these were only phase I studies, no results of efficacy were available. However, they paved the way for larger, phase II studies because they were found to be safe and lacking in serious adverse side effects. A phase II trial for 20 individuals was started a couple of months ago at San Francisco General Hospital where James Kahn is the principal investigator. A "phase I-extended" trial is occuring at the Miami Veterans Administration Hospital and will enroll a total of 10 people. Within the next few weeks, a multicenter trial administered through UCLA is set to begin. The sites involved will be LA (10 patients), Miami Beach (five patients) and Rush Medical Center in Chicago (five patients). The trial is being sponsored by Applied Immunosciences (AIS). Patients must have greater than 200 CD8 cells (no limit on the number of CD4 cells) and have biopsy-proven Kaposis's Sarcoma (KS). The procedure is as follows. First blood is taken, the red blood cells are separated from the other components and then returned to you at that same time (phoresis). Then there is a period of 10 to 14 days while AIS first fractionates the CD8 cells from the other white blood cells and then "expands" them. All populations of CD8 cells are expanded, not just certain subpopulations 7. These expanded CD8 cells are then reinfused back into the individual from which they came. Interleukin 2 (IL-2) is then infused via a "pump" mechanism which delivers it in small amounts over a five day period. Then there follows a period of "rest" of about one to two weeks prior to the next phoresis. There are to be five cycles in these trials. One individual who is just starting his fifth phoresis is doing well. He reports that his CD8 cells have increased somewhat and that he has had a definite decrease in the size of some but not all of his KS lesions. He notes that due to the slow rate of IL-2 infusion via the pump, he has had no adverse effects from the IL-2. In the early phase I studies, it was noticed that the most profound effect of this procedure occurred in a person with KS. Also, the lesions serve as a readily visible marker of any anti-KS effect this procedure is having. This technology is exciting and is also being tried on other cancers, e. g. renal carcinoma. Hopefully before the end of the year, there will be results available from these trials. References: 1. P. C. Doherty, et al. 1984. Advances in Cancer Research 42:1. 2. R. M. Zinkernagel and P. C. Doherty. 1979. Advances in Immunology 27:51. 3. C. M. Walker, et al. 1986. Science 234:1563-1566. 4. M. Fiala, Kermani V, & Gornbein J. 1992. Research in Immunology 143:903-907. 5. B. D. Walker, et al. 1987. Nature 328:345-348. 6. VII International Conference on aids. 1991. Florence, Italy. Th. B. 83. 7. Applied Immunosciences, personal communication.