Autoimmune syndrome after induction of neonatal tolerance to I‐E antigens

Abstract

Neonatal injection of semiallogeneic spleen cells induces a state of specific tolerance to the parental alloantigens, but also the development of an autoimmune syndrome known as host-versus-graft disease (HVGD). The autoimmune features are a consequence of the allogeneic cooperation between persisting alloreactive host T helper type 2 (TH2) cells and donor semiallogeneic B cells. It has been established that I-A alloantigens play a central role in the triggering of this HVGD. Here it was investigated if I-E antigens, which have shown functional differences, regarding autoimmunity and alloreactivity, with respect to I-A antigens, are also able to trigger this autoimmune syndrome. The injection of spleen cells from [B10.A(4R) x B10.A(2R)]F1 (I-E+) hybrid mice into newborn B10.A(4R) (I-E-) mice was accompanied by the establishment of chimerism and also by the development of a characteristic, but moderated, HVGD. The weak intensity of this HVGD is likely due to the moderation of the alloreactive responses induced against I-E molecules. Moreover, the marked increase in the levels of IgE and in the titers of anti-DNA IgG1 antibodies strongly suggest that alloreactive TH2 cells play also a main role in the autoimmune syndrome following tolerization to I-E antigens. Therefore, it is concluded that the I-E and I-A isotypes are functionally similar with respect to the allogeneic cellular interactions that account for the HVGD.

Completely allogeneic spleen cells induced cytolytic neonatal tolerance to alloantigens, but failed to establish allo‐helper interactions with host T cells

“…A(4R)]F 1 spleen cells 17. Similar results were obtained in B10.A(4R) mice receiving B10.A(2R) spleen cells (A. Gonzalez et al, unpublished data).…”

“…Interestingly, this lupus-like disease occurs exclusively if donor and host differ in either I-A or I-E MHC class II molecules. 16,17,19 We show here that completely allogeneic donor C57BL/6 (H- In various experimental models of allogeneic organ transplantation, graft rejection is accelerated when donor and recipient are completely allogeneic with respect to situations in which they share some MHC antigen. 2,6 However, our results confirm that during the neonatal period cytolytic T cells are efficiently tolerized by completely allogeneic cells as well as with semi-allogeneic cells.…”

“…Interestingly, this lupus-like disease occurs exclusively if donor and host differ in either I-A or I-E MHC class II molecules. 16,17,19 We show here that completely allogeneic donor C57BL/6 (H-2 b ) B cells fail to co-operate with donor CD4 + T cells for autoAb production, but are capable of inducing cytolytic tolerance to H-2 b alloantigens as efficiently as semi-allogeneic (C57BL/6 2 BALB/c)F 1 (H-2 b/d ) B cells. We also found that alloreactive BALB/c CD4 + T cells generated against (C57BL/6 2 BALB/c)F 1 B cells were deficient in the activation of C57BL/6 B cells.…”

“…10,14 The activation of alloreactive host Th2 cells in these mice has been evidenced in vitro by the demonstration of a 10-fold increase in the frequency of interleukin-4 (IL-4)-producer alloreactive precursors together with a decrease in the frequency of IL-2-producer cells. 24 In vivo evidence of this alloreactive Th2 cell activity includes the marked production of IgG1 and IgE in tolerized mice, 10,15,17 and the prevention of autoimmune manifestations after treatment with an anti-IL-4 monoclonal antibody. 12 According to these results, Powell & Streilein 24 have proposed that alloreactive host Th2 cells could play an active role in the maintenance of neonatal tolerance to alloantigens.…”

“…[10][11][12][13][14][15] Several in vivo studies have demonstrated that the recognition of either I-A or I-E MHC alloantigens, but not MHC class I or non-MHC alloantigens, is responsible for the development of HVGD. [16][17][18][19] The aim of this study was to evaluate whether alloreactive host T cells recognize completely allogeneic MHC molecules on donor cells as efficiently as semi-allogeneic MHC molecules, to induce cytolytic tolerance to H-2 alloantigens and to develop a HVGD. To this end, BALB/c mice were injected at birth with Thy-1-depleted spleen cells from C57BL/6 mice, either alone or in combination with Thy-1-depleted spleen cells from (BALB/ c 2 ) and (BALB/c 2 BC20)F 1 (IgCH-1 a ) mice, as described elsewhere.…”