DEFECTIVE CYTOKINE PRODUCTION FOLLOWING AUTOLOGOUS STEM-CELL TRANSPLANTATION FOR SOLID TUMORS AND HEMATOLOGIC MALIGNANCIES REGARDLESS OF BONE-MARROW OR PERIPHERAL ORIGIN AND LACK OF EVIDENCE FOR A ROLE FOR INTERLEUKIN-10 IN DELAYED IMMUNE RECONSTITUTION

A substantial body of evidence accumulated in recent years indicates a protracted delay in immune reconstitution following autologous stem c ell transplantation. In order to investigate the cellular basis of thi s phenomenon, peripheral blood mononuclear cells were studied from rec ipients of autologous stem cell transplantation for solid tumors and h ematological malignancies. On stimulation with phytohemagglutinin and phorbol 12-myristate 13-acetate, transplant-derived peripheral blood m ononuclear cells demonstrate statistically significant depressed produ ction of interleukin 3 (IL-3), IL-4, granulocyte-macrophage-colony-sti mulating factor, and gamma-interferon as compared to normal controls, during the first 6 months following engraftment, which recover to norm al levels 6 months or more posttransplant. When the overall group of t ransplant recipients is compared to the control group, there is a stat istically significant lower production of IL-2. In addition, no differ ences were observed regardless of the source of the engrafted stem cel ls, whether from bone marrow alone (autologous bone marrow transplanta tion), from peripheral blood stem cells alone, or from a combination o f autologous bone marrow transplantation and peripheral blood stem cel ls. The defect persisted past 6 months postengraftment. Transplant-der ived peripheral blood mononuclear cells were stimulated with combinati ons of either phytohemagglutinin plus the calcium ionophore A23187, th ereby circumventing the requirement for accessory cell function, or wi th phorbol 12-myristate 13-acetate plus anti-CD28 monoclonal antibody, mimicking the CD28-B7 cell surface-ligand interaction capable of trig gering and stabilizing IL-2 gene transcription. In both situations, de creased production of IL-2 as compared to controls was observed in ind ividuals within 6 months of transplantation, Quantitative polymerase c hain reaction indicates that decreased transcription of IL-2 mRNA foll owing transplantation is not due solely to a decrease in the absolute numbers of CD4(+) T-cells but is secondary to reduced numbers of trans cript copies per cell. Production of IL-10 was found to be decreased r egardless of whether the autologous graft was of bone marrow or periph eral blood origin. These findings are consistent with the conclusion t hat: (a) multiple dysregulations exist in the production of cytokines important in immune homeostasis; (b) a defect occurs at or prior to th e level of transcription of IL-2 mRNA; (c) IL-10 does not play a direc t role in the pathogenesis of posttransplantation immunosuppression; a nd (d) there is no evidence that peripheral blood stem cells may be su perior to bone marrow-derived stem cells in accelerating immune recons titution.