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. 1999 Apr 27;96(9):5159-63.
doi: 10.1073/pnas.96.9.5159.

The 60-kDa heat shock protein modulates allograft rejection

O S Birk  1 , S L Gur, D Elias, R Margalit, F Mor, P Carmi, J Bockova, D M Altmann, I R Cohen
Affiliations

The 60-kDa heat shock protein modulates allograft rejection

O S Birk et al. Proc Natl Acad Sci U S A. .

Abstract

Allograft rejection is a process of immune reactivity triggered by foreign transplantation antigens. We now demonstrate that the 60-kDa heat shock protein (hsp60), a molecule that is identical in the donor and the recipient, can regulate allograft immunity. In wild-type mice, hsp60 expression was greatly enhanced in allografts being rejected. By using MHC class II (Ealpha) promoter hsp60 transgenic mice either as donors of skin with enhanced expression of hsp60, or as allograft recipients with decreased hsp60 autoimmunity, we found that augmented expression of mouse hsp60 in the allograft accelerated its rejection, whereas reduced autoimmunity to mouse hsp60 in graft recipients delayed the process. Moreover, in nontransgenic mice, therapeutic administration of hsp60 or hsp60 peptides, known to modulate naturally occurring hsp60 autoimmunity, led to delayed allograft rejection. Thus, we demonstrate that hsp60 expression and hsp60 autoimmunity can influence and modify the immune response to foreign antigens. Hence, autoimmunity to self-hsp60 epitopes is not necessarily an aberration, but may serve physiologically and therapeutically to modulate foreign immunity.

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Figures

Figure 1
Figure 1
Western blot analysis of hsp60 expression in mouse skin. Lanes 1–4 show hsp60 expression during rejection of BALB/c (H-2d) skin removed 10 days after transplantation to allogeneic NOD (H-2g7) mice. Lanes 5–8 show the expression of hsp60 in BALB/c skin transplanted 10 days earlier to syngeneic BALB/c mice. Lane 9 shows the spontaneous expression of hsp60 in untransplanted Eα.hsp60 transgenic NOD skin. Lane 10 shows the expression of hsp60 in untransplanted wild-type NOD skin.
Figure 2
Figure 2
Expression of hsp60 affects the rejection of skin allografts. (A, Left) Eα.hsp60 transgenic skin is not rejected when transplanted to wild-type NOD mice. (A, Right) Eα.hsp60 transgenic mice do not reject wild-type skin. (B, Left) The accelerated rejection (P < 0.0001) of Eα.hsp60 transgenic NOD skin (◊) compared with wild-type NOD skin (□) transplanted to BALB/c mice. (B, Right) The accelerated rejection (P < 0.038) of Eα.hsp60 transgenic male NOD skin transplanted to HY incompatible, wild-type female NOD mice. (C, Left) The delay in rejection (P = 0.004) of allogeneic C57BL/6 (H-2b) skin by Eα.hsp60 transgenic NOD mice (H-2g7). (C, Right) The delay in rejection (P = 0.001) of BALB/k (H-2k) skin by Eα.hsp60 transgenic mice. Each group contained 10–12 mice. ◊, Eα.hsp60 recipients; □, control wild-type mice. The mice used in these and other experiments in the paper were 2 months old.
Figure 3
Figure 3
Spontaneous T cell proliferation of wild-type or hsp60-transgenic NOD mice to hsp60 peptides. Groups of six 2-month-old mice were tested individually for spontaneous reactivity to hsp60 peptides p278, p277, and MT-p278, and to no added peptide (control). Compared with wild-type NOD mice, the Eα.hsp60 NOD transgenics manifest a lack of spontaneous T cell reactivity to the self-hsp60 peptide p277, but their spontaneous T cell reactivity to a foreign T-cell epitope in NOD mice (18), the mycobacterial hsp60 peptide MT-p278, is not diminished. The mouse homologue of MT-p278, p278, is not a T cell epitope in NOD mice.
Figure 4
Figure 4
Treatment with hsp60 induces delayed rejection of skin allografts. C57BL/6 (H-2b) mice (A) or wild-type NOD (H-2g7) mice (B) were treated with a single dose of recombinant full-length hsp60 (50 μg in IFA; Sigma) administered s.c. into the back 2 weeks before transplantation of BALB/c (H-2d) skin. Control mice were untreated (□) or treated with IFA containing 50 μg of the recombinant control glutathione transferase (▵). The differences in rejection between treatment with hsp60 (●) and the controls, determined by using the Wilcoxon test, were significant (P < 0.05 for A and P < 0.0001 for B). Each group contained 10–12 mice. The experiment was repeated three times with similar results.
Figure 5
Figure 5
Treatment with hsp60 peptides induces delayed rejection of skin allografts. Wild-type NOD (H-2g7) mice were treated with various hsp60 peptides (50 μg) in IFA. Control mice were untreated (□) or were treated with IFA containing peptide p11, which is nonimmunogenic in NOD mice (♦) (26). The differences in rejection between treatment with hsp60 epitope peptides p12 (■) or p277 (▵) and the controls were significant (P < 0.0001). The experiment was repeated three times with similar results.
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