J. M. Ali1, M. C. Negus1, E. M. Bolton1, K. Saeb Parsy1, J. A. Bradley1, G. J. Pettigrew1 1Department of Surgery, University of Cambridge
Introduction:
Uniquely alloantigen is recognised by two pathways: the direct and indirect. The indirect pathway is believed to be long-lived, and thought of as a single entity. Here we address how indirect responses against different alloantigens differ in their strength and longevity.
Methods:
A murine model of cardiac transplantation was utilised [bm12.Kd.IE to C57BL\6]. Indirect CD4 T-cell allorecognition of donor MHC class I and II, and H-Y minor antigen was assessed by quantifying proliferation of adoptively transferred monoclonal T-cell receptor transgenic T-cells (TCR75, TEa and Mar respectively) at various time points. Antigen presentation by dendritic cells (DC) was assessed by selective depletion using diphtheria toxin; and B-cells, by administering depleting anti-CD20 monoclonal antibody.
Result:
Indirect pathway responses were heterogeneous. Whereas the indirect response against class I alloantigen was long-lived and persistently strong, the class II indirect response was remarkably short-lived (decaying within two weeks), because it is dependent upon donor B-cells and DC’s as a source of class II alloantigen, and these are cleared rapidly by the recipient. The longevity of the class I indirect response reflected on-going antigen presentation, but notably B-cells played an increasingly important role, perhaps reflecting antigen-specific expansion. Finally, the indirect response against minor H-Y antigen was long-lived but weakened progressively.
Conclusion:
Although thought of as a single entity, our results highlight that indirect allorecognition comprises a number of responses that vary in duration and strength according to target alloantigen. Targeting those responses that are long-lived may be particularly effective at preventing chronic rejection.