Potential use of interleukin-6 in bone marrow transplantation: effects of recombinant human interleukin-6 after syngeneic and semiallogeneic bone marrow transplantation in mice

Abstract

The potential of recombinant glycosylated human interleukin-6 (rhIL-6) for enhancing immunohematopoietic reconstitution and survival after syngeneic and semiallogeneic bone marrow transplantation (BMT) in BALB/c mice subjected to total body irradiation (TBI) was investigated. rhIL-6 produced enhanced reconstitution of white blood cells as assessed on days 8 and 14 after syngeneic BMT and of platelets as assessed on day 10. Moreover, rhIL-6 treatment produced significant improvement of survival in lethally irradiated mice receiving either syngeneic or semiallogeneic BMT with limiting number of BM cells. This effect of IL-6 was not seen with large BM cell inocula producing high survival by themselves. rhIL-6 showed no toxic effects and did not affect the survival of mice that were lethally irradiated but not reconstituted by BM cells. However, the sensitivity of mice to sublethal irradiation was increased by rhIL-6 in the absence of BM cell transplantation. In experimental conditions inducing graft-versus-host disease (GVHD), in which lethally irradiated (BALB/c x C57BL/6)F1 mice received mixtures of BM and spleen cells from C57BL/6 donors, rhIL-6 was found to enhance GVHD manifestations. No consistent enhancement of T-cell in vitro proliferative responses to allogeneic spleen cells or T- and B-cell-dependent mitogens were seen in the splenocytes obtained from recipients of syngeneic or semiallogeneic BMT. Our data suggest that rhIL-6 may be useful in BMT procedures to enhance thrombopoiesis and hematologic recovery, as well as to increase overall survival rates. In addition, the potentiation of GVHD, which is considered to correlate with graft-versus-leukemia effects, may be of interest in enhancing GVHD-dependent antitumor effects in protocols combining radiochemotherapy with BMT.

The Role of Intensive Therapy and Autologous Blood and Marrow Transplantation for Chemotherapy‐Sensitive Relapsed and Primary Refractory Non‐Hodgkin’s Lymphoma: Identification of Major Prognostic Groups

“…Bulky disease and poor performance status are known adverse prognostic factors (Bosly et al, 1992;Petersen et al, 1990;Freedman & Nadler, 1993;Takvorian et al, 1987;Phillips et al, 1990;Conde et al, 1994;Milpied et al, 1994) and by excluding patients with these characteristics our cohort is selected for a more favourable group. Previous studies of ABMT for NHL have examined other prognostic factors such as transformation from low to intermediate/high grade histology, previous marrow involvement, prior radiotherapy, LDH, age and number of previous chemotherapy regimens, but give conflicting results (Bosly et al, 1992;Appelbaum et al, 1987;McMillan & Goldstone, 1991;Appelbaum et al, 1987;Petersen et al, 1990;Takvorian et al, 1987;Philip et al, 1987;Freedman et al, 1990;Vose et al, 1993;Phillips et al, 1990;Givon et al, 1994). When we examined a number of potential prognostic factors by multivariate regression analysis we identified remission status at transplant as the single most important determinant of survival and PFS after transplant.…”

“…Consequently, novel additional or alternative approaches are needed for those patients who only achieve a PR with conventional-dose salvage therapy. These include the use of multiple cycle intensive therapy (Van Besien et al, 1994), modifiers of multidrug resistance (Frei & Freireich, 1993), allogeneic marrow or blood cell transplantation (Ratanatharathorn et al, 1994;Demirer et al, 1995;Mendoza et al, 1995), immunomodulation therapy (Givon et al, 1994;Soiffer et al, 1993;Gisselbrecht et al, 1994;Weisdorf et al, 1994), immunotoxin therapy (Grossbard et al, 1992;Vallera, 1994) and therapeutic radioimmunoconjugates (Parker et al, 1990).…”

A pilot study of single nucleotide polymorphisms in the interleukin-6 receptor and their effects on pre- and post-transplant serum mediator level and outcome after allogeneic stem cell transplantation

“…In addition, it has been shown recently that polymorphisms in Janus kinase 2 (JAK2), which is directly downstream of the IL‐6R, are associated with increased risk of GVHD . Experimental studies support the hypothesis that there are close links between increased IL‐6 activity, T cell development and end organ damage after ASCT . Finally, IL‐6 is a pleiotrophic cytokine that is involved in regenerative processes, especially in the liver and the gastrointestinal tract, two organs that are commonly affected in GVHD .…”

Rescue from lethal acute radiation syndrome (ARS) with severe weight loss by secretome of intramuscularly injected human placental stromal cells

“…77 This could also aid the BM reconstitution after syngeneic BMT, leading to the extension of IL-6 therapy from irradiated rodents and primates to the clinical practice. 78 Whereas murine IL-6 was not detectable in the few surviving irradiated control mice before the end of the second week post-irradiation, the mice treated with PLX-RAD cells expressed both human and murine IL-6 levels as early as day 2 after irradiation. This early secretion of both IL-6 and IL-8 by PLX-RAD cells in response to ARS-related stress signals was associated with significantly lower levels of murine IL-6 secretion within the first week.…”

“…The activities of IL‐6 as an acute‐phase induced cytokine include the triggering haematopoiesis by inducing multi‐lineage HSC stimulation and acceleration of the regeneration of WBC, platelets and RBC in high dose irradiated mice . This could also aid the BM reconstitution after syngeneic BMT, leading to the extension of IL‐6 therapy from irradiated rodents and primates to the clinical practice …”