Ronald E. Gress

Association of Serum Interleukin-7 Levels With the Development of Acute Graft-Versus-Host Disease

PURPOSEnMorbidity from acute graft-versus-host disease (GVHD) limits the success of allogeneic hematopoietic stem-cell transplantation (HSCT) to treat malignancy. Interleukin-7 (IL-7), the principal homeostatic cytokine for T cells, is required for acute GVHD in murine models. In contrast to inflammatory cytokines (eg, IL-2, tumor necrosis factor alpha), IL-7 has not been studied extensively in the clinical transplant setting relative to its relationship with acute GVHD.nnnPATIENTS AND METHODSnWe evaluated the association of serum IL-7 levels with acute GVHD in 31 patients who were uniformly treated in a prospective clinical trial with reduced-intensity allogeneic HSCT from human leukocyte antigen-identical siblings. GVHD prophylaxis consisted of cyclosporine and methotrexate. Serum IL-7 levels and lymphocyte populations were determined at enrollment, the day of transplantation before the allograft infusion, and at specified intervals through 12 months post-transplantation.nnnRESULTSnAs expected, IL-7 levels were inversely correlated with T-cell populations (P < .00001). Acute GVHD was significantly associated with higher IL-7 levels at day +7 (P = .01) and day +14 (P = .00003) post-transplantation as well as with the allograft CD34(+) cell dose (P = .01). IL-7 levels at day +14 also correlated with the severity of acute GVHD (P < .0001). In logistic regression models, these factors were highly sensitive (up to 86%) and specific (100%) for classifying whether patients developed acute GVHD.nnnCONCLUSIONnThese data support preclinical observations that IL-7 plays a critical role in inducing acute GVHD and provide a rational basis for novel approaches to prevent and treat acute GVHD through modulation of the IL-7 pathway.

Background to hematopoietic cell transplantation, including post transplant immune recovery

Background to hematopoietic cell transplantation, including post transplant immune recovery

Natural killer cell receptor repertoire following HLA-matched allogeneic hematopoietic stem cell transplantation

6635 Background: Following hematopoietic stem cell transplantation (HSCT), natural killer (NK) cells are among the first lymphocytes to recover, returning to normal levels within six weeks after HSCT. NK cells may mediate anti-tumor effects and regulate graft versus host disease (GVHD); modulation of the relative frequency and intensity of expression of the cytotoxic NK receptors may influence NK activity post transplant.nnnMETHODSnWe compared the NK receptor expression in seven patients at one month following non-myeloablative HLA-matched allogeneic HSCT with that of donors and healthy volunteers. NK cells were divided into two subsets based on expression of CD56 and CD16. Both subsets were assessed for three main classes of receptors that trigger or inhibit cytotoxicity: natural cytotoxicity receptors (NCR), killer immunoglobulin-like receptors (KIR) and C-type lectin receptors.nnnRESULTSnCompared to donors, the expression of the NCR NKp46 increased significantly in all patients, whereas NKp30 increased in the CD 56+ bright subset only in patients that developed acute GVHD. Expression of KIR receptors (CD158A, CD158B) did not change or decreased slightly. In contrast the C-type lectin receptor CD 94 was upregulated on most NK cells. The heterodimeric partners of CD94, NKG2A and NKG2C, were also increased, but the increase in frequency of cells expressing the inhibitory receptor NKG2A was greater than that of the activating receptor NKG2C. The homodimeric activating receptor NKG2D increased in all patients. No significant differences in NK receptor expression between the donors and healthy volunteers was observed Conclusions: These results demonstrate changes in the NK receptor repertoire during the early post-transplant period that may have an impact on NK cells mediated cytotoxicity. No significant financial relationships to disclose.