Human allograft acceptance is associated with immune regulation
A.M. VanBuskirk, … , R.P. Pelletier, C.G. Orosz
A.M. VanBuskirk, … , R.P. Pelletier, C.G. Orosz
Published January 1, 2000
Citation Information: J Clin Invest. 2000;106(1):145-155. https://doi.org/10.1172/JCI9171.
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Human allograft acceptance is associated with immune regulation

Abstract

The ultimate goal of transplantation is drug-free allograft acceptance, which is rarely encountered in transplant recipients. Using a novel human-to-mouse “trans vivo” delayed-type hypersensitivity assay, we assessed donor-reactive cell-mediated immune responses in kidney and liver transplant patients, four of whom discontinued all immunosuppression. One of these subjects (J.B.) rejected his graft after 7 years of stable function, while the others (D.S., R.D., M.L.) continue to have excellent graft function 5, 28, and 4 years after the cessation of immunosuppression. PBMCs from J.B. exhibited strong responses to both donor and recall antigens whereas PBMCs from patients D.S., R.D., and M.L. responded strongly to recall, but not donor, antigens. Furthermore, when donor and recall antigens were colocalized, the recall response in these three patients was inhibited. This donor antigen–linked nonresponsiveness was observed in four other patients who are still maintained on immunosuppression. The weakness of donor-reactive DTH responses in these patients is due to donor alloantigen-triggered regulation that relies on either TGF-β or IL-10. In D.S., regulation is triggered by a single donor HLA Class I antigen, either in membrane-bound or soluble form. This demonstrates that allograft acceptance in humans is associated with an immune regulation pattern, which may be useful in the diagnosis and/or monitoring of transplant patients for allograft acceptance.

Authors

A.M. VanBuskirk, W.J. Burlingham, E. Jankowska-Gan, T. Chin, S. Kusaka, F. Geissler, R.P. Pelletier, C.G. Orosz

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Figure 3

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Effect of cytokine neutralization on donor-reactive DTH. (a) Eight milli...
Effect of cytokine neutralization on donor-reactive DTH. (a) Eight million PBMCs from patient D.S. were mixed with 10 μg donor or self antigen or 105 irradiated donor-derived EBV-transformed LCL and 25 μg of either control rabbit IgG or rabbit anti-human TGF-β IgG and injected into the footpads of Balb/c SCID mice. Swelling was measured after 24 hours. Results are expressed as the change over the swelling induced by injection of PBMCs alone. To determine the effect of neutralizing antibodies to IL-10, 8 million PBMCs from patient D.S. were mixed with 10 μg donor antigen or 105 irradiated donor-derived EBV-transformed LCL and 25 μg of either control goat IgG or goat anti-human IL-10. Swelling was measured after 24 hours, as described above. (b) Eight million PBMCs from patient A.J. were mixed with 10 μg donor antigens and 25 μg of either control rabbit IgG or rabbit anti-human TGF-β IgG and injected into the footpads of SCID mice. Swelling was measured as described above. To assess the effect of neutralizing antibodies to IL-10, PBMCs from patient A.J. were mixed with donor or self antigens and 25 μg of either control Ig or anti–IL-10. The results shown are from three separate experiments. In two experiments, the anti–IL-10 was a mAb with a mouse IgG-1 control. In the third experiment, goat anti-human IL-10 and goat IgG were used as the specific antibody and control, respectively. The results were not significantly different whether the polyclonal antibody or mAb was used.