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In previous prospective studies conducted in our department, PCR was used to detect the three β-herpesviruses, human cytomegalovirus (HCMV), and human herpesviruses 6 and 7 (HHV-6 and HHV-7) in the blood of solid organ transplant patients. The viruses were commonly detected post-transplantation, and HCMV and HHV-6 were independently associated with graft rejection in liver recipients. HHV-7 was also associated with increased episodes of rejection in renal transplant patients. To better understand the role of these viruses in graft rejection, in situ techniques including in situ hybridisation (ISH) and immunohistochemistry (IHC) were developed to detect these viruses in renal and liver allograft biopsies from patients in the original prospective studies. HCMV DNA was detected in a significant proportion of liver and renal biopsies (approximately 50%) by ISH, with detection being widespread especially in renal allografts. The presence of HCMV DNA in the biopsies is likely to represent low level HCMV replication not detectable by IHC. HCMV was not statistically associated with either renal or liver allograft rejection by ISH. It remains possible that HCMV infection in the graft leads to dysfunction and is clinically interpreted as allograft rejection. HHV-6 and HHV-7 were not detected in any allografts by ISH or IHC. In addition, an uncommon form of HHV-6 persistence is characterized by high viral loads in blood and integration of viral sequences into host cell chromosomes. Fluorescence in situ hybridisation (FISH) was developed to examine integration events in a healthy individual with a consistently high HHV-6 load and also in a case of genetic transmission of integrated virus through stem cell transplantation. In the former individual, integrated HHV-6 was identified on chromosome lip 15.5 and in the latter shown in the donor and the recipient (post-transplantation only) on chromosome 17pl3.3. The confounding effect of HHV-6 integration must be considered when investigating novel disease associations of HHV-6.

A major conceptual shift in immunology has been the recent discovery of regulatory T- cells (Treg), of which C04+Foxp3+ cells are already known to be essential to self- tolerance. Their role in transplant tolerance remains unproven due to the absence of a natural cell surface marker by which they can be manipulated in vivo. A transgenic B6.Foxp3hCD2 mouse was created to express an artificial GPI-anchored human C02/ C052 surface fusion protein under the control of the Foxp3 promoter. Monoclonal antibodies directed against the human C02 and human C052 were used in B6.Foxp3hCD2 mice to isolate and ablate Foxp3+ Treg. C04+Foxp3+ cells were found to be crucial for transplant tolerance induced by non-ablative co-receptor and eo- tt stimulatory blockade. In tolerant animals, Foxp3+ Treg are constantly required to suppress effector T-cells still capable of causing tissue damage. Remarkably, tolerated tissue contains T-cells capable of rejecting it, but these are prevented from doing so by therapeutically induced Foxp3+ Treg. Finally, induced Foxp3+ cells sustain tolerance by converting naive T-cells into the next generation of Foxp3+ cells in the periphery, providing one potential mechanism by which infectious tolerance may operate in vivo.

The twentieth century was a time of a lot of advances in medicine, none more so than in the field of transplantation. Thanks to the pioneering work of many different people in a variety of different fields it is now possible to transplant bone marrow and solid organs. Transplantation is a truly multidisciplinary specialty where patient care is shared between physicians and surgeons. As in all medical specialties good nursing care is essential and requires a high degree of specialisation. Pathologists are key in post operative management in order to promptly diagnose problems so that treatment can be commenced with the minimum of delays.