Stephan D. Voss
| Years in MSTP | 1986-1994 |
|
PhD |
Human Oncology, 1992 |
|
Mentor |
Paul M. Sondel |
| Thesis Title |
Characterization of the IL-2 Receptors Expressed on Human l Lymphocytes Activated In Vivo During Systemic IL-2 Therapy |
| Residency |
Radiology, Beth Israel Deaconess, Boston |
| Fellowship | Pediatric Radiology, Children's Hospital of Boston |
| Investigative Research | Molecular and oncologic imaging |
| Current Position |
Assistant professor of radiology, Children's Hospital of Boston |
Thesis Abstract
The cellular and molecular mechanisms of Interleukin 2 (IL-2) recognition and action occurring in vivo in cancer patients receiving IL-2 therapy remain uncertain. IL-2 activates cells through membrane IL-2 receptors consisting of at least alpha and/or beta subunits. Both high-affinity (alpha beta) and intermediate-affinity (beta) receptors are involved in mediating biological signals.
Initial studies documented that high levels of a soluble form of the IL-2R alpha chain (sTac) were released into the sera of patients receiving IL-2 therapy. However, post-IL-2 therapy NK cells showed minimal sTac release, even though this was the primary population of IL-2 responsive cells recovered following IL-2 therapy, suggesting these cells were not responding through high-affinity IL-2 receptors.
Increased expression of the IL-2R beta chain was subsequently identified on post-therapy NK cells, suggesting these cells may have acquired increased functional IL-2 responsiveness due to up-regulation of intermediate-affinity cell-surface IL-2 receptors. Only low levels of IL-2 binding were detected in 125I-IL-2 binding assays on post-therapy NK cells, however, and it was concluded that some other component, in addition to the beta chain, was required in order to constitute an intermediate-affinity IL-2 receptor.
Using an anti-beta chain mAb to precipitate IL-2/IL-2 receptor complexes, an IL-2R gamma subunit was subsequently identified. Only low levels of gamma chain relative to beta chain were detected on post-IL-2 therapy NK cells, consistent with the hypothesis that gamma chain is required for formation of intermediate-affinity IL-2 receptors and that it was absent from the majority of the IL-2 receptors expressed on post-therapy NK cells.
The surprising finding was also made that the IL-2R gamma chain is able to directly interact with IL-2 and may thus influence receptor affinity by contributing contact sites for IL-2 binding. This unexpected finding has allowed the development of a revised model of IL-2 receptor structure depicting the predicted sites of interaction of IL-2 with the respective alpha, beta, and gamma receptor subunits.
Thesis Publications
Farner NL, Voss SD, Leary TP, Gan J, Hakimi J, Evans G, Ju G, Sondel PM. Distinction between gamma c detection and function in YT lymphoid cells and in the granulocyte-macrophage colony-stimulating factor-responsive human myeloid cell line. Blood 86:4568-4578, 1995.
Farner NL, Voss SD, Sondel PM. X-linked severe combined immunodeficiency disease and the gamma c receptor component: prospects for molecular diagnosis. Clin Diagn Lab Immunol 2:518-523, 1995.
Sondel PM, Voss SD, Hong R. Addendum to SCID, interleukin-2, and the interleukin-2 receptor review. Blood 84:667-668, 1994.
Voss SD, Hong R, Sondel PM. Severe combined immunodeficiency, interleukin-2 (IL-2), and the IL-2 receptor: experiments of nature continue to point the way. Blood 83:626-635, 1994.
Kaur I, Voss SD, Gupta RS, Schell K, Fisch P, Sondel PM. Human peripheral gamma delta T cells recognize hsp60 molecules on Daudi Burkitt's lymphoma cells. J Immunol 150:2046-2055, 1993.
Voss SD, Leary TP, Sondel PM, Robb RJ. Identification of a direct interaction between Interleukin 2 and the p64 Interleukin 2 receptor ƒ× chain. Proc Natl Acad Sci USA 90:2428-2432, 1993.
Voss SD, Sondel PM, Robb RJ. Characterization of the interleukin 2 receptors (IL-2R) expressed on human natural killer cells activated in vivo by IL-2: association of the p64 IL-2R gamma chain with the IL-2R beta chain in functional intermediate-affinity IL-2R. J Exp Med 176:531-541,1992.
Bogner MP, Voss SD, Bechhofer R, Hank JA, Roper M, Poplack D, Hammond D, Sondel PM. Serum CD25 levels during interleukin-2 therapy: dose dependence and correlations with clinical toxicity and lymphocyte surface sCD25 expression. J Immunother 11:111-118, 1992.
Voss SD, Robb RJ, Weil-Hillman G, Hank JA, Sugamura K, Tsudo M, Sondel PM. Increased expression of the interleukin 2 (IL-2) receptor beta chain (p70) on CD56+ natural killer cells after in vivo IL-2 therapy: p70 expression does not alone predict the level of intermediate affinity IL- 2 binding. J Exp Med 172:1101-1114, 1990.
Weil-Hillman G, Voss SD, Fisch P, Schell K, Hank JA, Sosman JA, Sugamura K, Sondel PM. Natural killer cells activated by interleukin 2 treatment in vivo respond to interleukin 2 primarily through the p75 receptor and maintain the p55 (TAC) negative phenotype. Cancer Res 50:2683-2691,1990.
Voss SD, Hank JA, Nobis CA, Fisch P, Sosman JA, Sondel PM. Serum levels of the low-affinity interleukin-2 receptor molecule (TAC) during IL-2 therapy reflect systemic lymphoid mass activation. Cancer Immunol Immunother 29:261-269, 1989.
Voss SD, Weil-Hillman G, Hank JA, Sosman JA, Sondel PM. The clinical immunobiology of interleukin-2: potential modified uses for improved cancer treatment. Bull N Y Acad Med 65:93-110, 1989.