Immunologic Aspects of Acute Cutaneous Graft-Versus-Host Disease: Decreased Density and Antigen-Presenting Function of Ia+ Langerhans Cells and Absent Antigen-Presenting Capacity of Ia+ Keratinocytes

Abstract

Cutaneous graft-versus-host disease (GVHD) provides a unique model for studying the pathogenesis of several important lymphocyte-mediated skin diseases. Morphologic studies have suggested that Ia antigen (Ia)-bearing epidermal Langerhans cells (LC) may be specific targets for destruction in these conditions. Keratinocytes synthesize and express Ia in GVHD and some other lymphocyte-mediated skin disorders; Ia+ keratinocytes, constitutively able to secrete epidermal cell-derived thymocyte activating factor (ETAF)/interleukin 1, may possess antigen-presenting capacity, thus leading to enhanced cutaneous immune responses and disease chronicity. We therefore investigated the fate of Ia+ LC, and the potential antigen-presenting capacity of Ia+ keratinocytes, in a murine model of GVHD. Lethally irradiated C3H/He (H-2k) mice developed acute cutaneous GVHD, and expressed keratinocyte Iak, 8 days after injection of BALB/c (H-2d) bone marrow and spleen cells. Immunofluorescence studies showed a progressive decrease in the density of Ia+ epidermal LC during the evolution of GVHD. This decrease was paralleled by a progressive reduction in the allostimulatory capacity of GVHD epidermal cells (EC) in the allogeneic EC-lymphocyte reaction (ELR). The fall in the density of Ia+ LC, and in EC allostimulatory capacity in both primary and secondary ELRs, was consistently greater in GVHD mice than in mice treated only with x-irradiation. The allostimulatory capacity of GVHD and x-irradiated EC could not be restored by addition of indomethacin or exogenous ETAF to ELR cultures. The decreased allostimulatory capacity was not the result of inhibition of the ELR, since EC from GVHD and x-irradiated mice did not cause suppression when added to control ELR cultures. The capacity of EC to present ovalbumin, purified protein derivative of tuberculin, 2,4,6-trinitrobenzenesulfonic acid coupled to EC, and native cytochrome c (CYTc) to antigen-specific T-cell lines, clones, or hybridomas was reduced in x-irradiated mice and markedly decreased in GVHD mice. The capacity of EC from x-irradiated and GVHD mice to present CYTc fragment 81-104, which does not require further processing or catabolism by accessory cells, was similarly decreased. Taken together, the results indicate that: the function of LC is markedly and progressively impaired in acute GVHD; LC function is also decreased, but to a lesser extent, following x-irradiation alone; and Ia+ keratinocytes from lethally irradiated mice undergoing GVHD do not exhibit antigen-presenting capacity.