Specific Suppression of Lupus-Like Graft-Versus-Host Disease Using Extracorporeal Photochemical Attenuation of Effector Lymphocytes

Abstract

(C57BL/6 x DBA/2)F1 (B6D2F1) mice inoculated with parental DBA/2 (D2) splenocytes develop chronic stimulatory graft-versus-host reaction with many of the clinical manifestations of systemic lupus erythematosus. This investigation tested the ability of 8-methoxypsoralen (8-MOP) and ultraviolet A (UVA) light-treated D2 cells, primed to contain an expanded population of T cells specific for B6D2F1 major histocompatability complex antigens, to treat and/or prevent such systemic lupus erythematosus-like disease. 8-MOP/UVA-treated cells from B6D2F1-primed D2 donors were inoculated into B6D2F1 recipients weekly six to ten times, either before or after initiating graft-versus-host disease with normal D2 cells. A third group of B6D2F1 recipients were vaccinated weekly six times before disease initiation using 8-MOP/UVA-attenuated, B6D2F1-primed D2 cells that had been secondarily stimulated and expanded in vitro in the presence of irradiated B6D2F1 targets and interleukin-2. Control B6D2F1 mice were vaccinated with 8-MOP/UVA-treated D2 cells stimulated in vitro and/or in vivo with (C3H/HeJ x DBA/2)F1 cells. Only mice vaccinated with 8-MOP/UVA-attenuated D2-anti-B6D2F1 cells that were secondarily stimulated and expanded in vitro exhibited differences from controls when measured by the clinical parameters of ascites formation, and mean survival (p < 0.025). These groups also differed significantly in mean antinuclear antibody titer measured 14 weeks after disease initiation (p < 0.05). At 28 weeks, histologic evidence of systemic lupus erythematosus-like kidney disease was found only in the control group. These results indicate that photochemically attenuated D2-anti-B6D2F1 cells primed in vivo and secondarily stimulated and expanded in vitro are capable of vaccinating recipients against progression of graft-versus-host reaction-initiated systemic lupus erythematosus-like disease.

Identification of amplified clonal T cell populations in the blood of patients with chronic graft-versus-host disease: positive correlation with response to photopheresis

“…Experimental data acquired from animal autoimmune and transplantation studies suggest that photopheresed cells induce an antigen-specific immune response directed to pathogenic T cell populations without affecting general immunocompetence. [29][30][31] In our patients, however, no decrease or disappearance of the clonal population of T cells was observed after photopheresis. The mechanism by which photopheresis brings about clinical improvement in this situation therefore remains unclear, but could potentially involve modulation of T cell function.…”

Treating refractory chronic graft-versus-host disease with extracorporeal photochemotherapy

“…6,7 For instance, in (C57BL/6 Â DBA/2)F1 (B6D2F1) mice that, when inoculated with parental DBA/2 (D2) splenocytes, develop chronic stimulatory graft-versus-host reaction with clinical manifestations of systemic lupus erythematosus (SLE), inoculation of 8-MOP-UVA-radiation-exposed D2 splenocytes inhibited the progression of GvHD-initiated SLE-like disease that had been previously elicited by inoculation of unexposed D2 splenocytes. 15 Moreover, in a recent study with 10 cGvHD patients treated with ECP for two consecutive days every 2 weeks for 6-12 months, seven patients who achieved a clinical response (improvement in skin changes) had initially displayed clonal populations of alloreactive T cells by spectra type analysis, whereas nonresponding patients had not. 12 New research with cGVHD suggest that ECP leads to attenuation of Th1-mediated cytokine secretion, a shift in the DC1/DC2 ratio towards plasmacytoid rather than monocytoid dendritic cell profiles, and diminished dendritic-cell antigen responsiveness.…”

Extracorporeal photopheresis in chronic graft-versus-host disease

“…13 The administration of 8-MOP and UVA irradiated spleen and bone marrow cells to mice receiving allografts resulted in a significant attenuation of GVHD compared to littermates who received non-UVA irradiated cells, demonstrating an effect of UVA exposure on effectors of alloreactivity. 29 In another study, using C57BL/6 × DBA/2)F1 (B6D2F1) mice which, when inoculated with parental DBA/2 (D2) splenocytes, develop Table 1 Extracorporeal phototherapy: advantages, toxicities, uses and results 30 These results supported the concept that photoactivated T cells might be responsible for induction of a vaccine-like effect, although the putative anti-idiotype T cell populations have not been fully characterized.…”