Cytopenia and leukocyte recovery shape cytokine fluctuations after myeloablative allogeneic hematopoietic stem cell transplantation

Abstract

Background: Allogeneic hematopoietic stem cell transplantation is associated with profound changes in levels of various cytokines. Emphasis has been placed on conditioning-associated mucosal damage and neutropenia and associated bacterial translocation as the initiating conditions predisposing to acute graft-versus-host disease. The post-transplant period is, however, also associated with increases in certain homeostatic cytokines. It is unclear how much the homeostatic drive to lymphocyte recovery and the production of cytokines from the engrafting donor immune system determine cytokine fluctuations in the peri- and immediate post-transplant period. The aim of this study was to examine the contributions of the conditioning regimen, donor engraftment, infections, and graft-versus-host disease to fluctuations in cytokines involved in homeostasis and inflammation.

Design and methods: We examined the levels of 33 cytokines in relation to peri- and post-transplant events such as conditioning regimen, chimerism, and acute graft-versus-host disease in myeloablative, non-T cell-replete HLA-identical sibling donor stem cell transplantation for hematologic malignancies.

Results: We identified two cytokine storms. The first occurred following conditioning and reached peak levels when all the leukocytes were at their lowest concentrations. The second cytokine storm occurred concurrently with hematopoietic reconstitution and subsided with the achievement of full donor lymphocyte chimerism.

Conclusions: Our results indicate that both recipient-related and donor-related factors contribute to the changes in cytokine levels in the recipient following allogeneic hematopoietic stem cell transplantation. The study reported here was performed using plasma samples drawn from patients enrolled in the ClinicalTrials.gov-registered trials NCT00467961 and NCT00378534.

Figures

Figure 1.

Fluctuations of C-reactive protein (CRP), temperature, leukocytes, and cytokines around the time of transplant (indicated as a broken vertical line at day 0) show two separate patterns. (A) Dynamics of the main leukocyte subsets and homeostatic cytokines relative to the time of transplant. Each variable is plotted in log10 scale. Ranges within days −7 to +21 are: granulocytes, 0.002–20.18; lymphocytes, 0.002–2.307; monocytes, 0.001–2.084; G-CSF, 0.12–38310; IL-15, 0.84–170.2; MCP-1, 6.34–2918; IL-6, 1.72–3524; IL-7, 0.41–60.97; IL-1ra, 3.94–2170. Observations below the detection limit were replaced with the midpoint between 0 and the detection limit. (B) Individual measurements and mean curve over time for CRP and temperature. The inflammation indicator CRP and temperature both reach a maximum a week after infusion of the T cell-depleted transplant. CRP is plotted in log10 scale. Time is plotted in days relative to the time of transplantation. (C) Dynamics of inflammatory cytokines around the time of transplant shows a pattern directly correlated with leukocyte counts. The ranges within days −7 to 42 are: IFN-γ, 0.34–1677 pg/mL; IL-2, 0.24–48.77 pg/mL; TNF-α, 1.26–186.6 pg/mL; IL-1β, 0.08–10.01 pg/mL. Observations below the detection limit were replaced with the midpoint between 0 and the detection limit. Patients with all measurements below the detection limits were excluded.

Figure 2.

Days to peak levels of C-reactive protein (CRP) and cytokines. Patients with all measurements below detection limits have been excluded.