Seventeen years after successful small bowel transplantation: long term graft acceptance without immune tolerance

The first attempts at small bowel transplantation (SBT) in humans were disappointing¹,²,³ and characterised by severe graft rejection in spite of initially encouraging experience in animals.³,⁴,⁵ Major difficulties were encountered as: (1) the intestine is an immune organ harbouring most immune competent cells of the body; and (2) it is particularly vulnerable to ischaemia, not allowing time consuming HLA matching prior to transplantation (Tx). Therefore, Tx of intestinal allografts into fully immune competent recipients results almost inescapably in terminal graft rejection. With the introduction of tacrolimus in the 1990s, this difficulty was partially overcome, improving small bowel graft survival rates (70% at one year post Tx).⁶,⁷,⁸ However, on follow up, a large number of grafts are still lost, raising the question of long term success and benefit after SBT. Here we present the first patient with a 17 year follow up after isolated SBT.

A Caucasian infant girl with extreme short bowel secondary to neonatal volvulus was transplanted with an isolated intestinal graft on 18 March 1989 at the age of five months.⁹ The iso‐blood group O Rhesus positive transplant (two HLA class I and one class II mismatch, with negative T cell cross match) was derived from an anencephalic newborn girl. Immunosuppression was based on ciclosporin (CsA), prednisolone, azathioprine, and a single injection of rabbit antihuman thymocyte globulins (5 mg/kg) with an in situ flush of the SB graft with CsA. Four acute graft rejection episodes occurred, at days 82, 121, and 205, and 19 months post Tx, all of which responded favourably to medical therapy (OKT3, anti‐interleukin 2 receptor monoclonal antibodies, or rabbit antihuman thymocyte globulin combined with steroid pulses and transient bowel rest). Eight months after SBT, the infant was weaned off parenteral nutrition. Further complications included CsA induced hypertrichosis, gingival hyperplasia, a moderately severe Pneumocystis carinii pneumonia at two months, and cytomegalovirus infection five years post‐Tx. In 1998, nine years after SBT, the patient suffered another (fifth) rejection episode motivating a switch from CsA to tacrolimus that resulted in intestinal graft recovery. Since then, she has been leading a normal life (eating normally by mouth, 2–3 soft stools a day) without any further Tx related complications or hospital stays (except routine examinations evaluating graft function and monitoring for adverse reactions to IS, including tumour screening). Meanwhile, the girl has completed puberty (final height 160 cm (median percentile) and weight 45 kg (−1 SD)).

Evaluation of graft function at 15.5 years post Tx showed a total energy absorption rate of 93% using calorimetric analyses (carbohydrates 94%, nitrogen 86%, and lipids 93%, with a daily oral caloric intake of 2300 kcal in 2005). On histology (fig 1), we observed normal intestinal cytoarchitecture and villi; however, the lamina propria was infiltrated with mononuclear, mainly CD3 positive T cells. Some of these cells stained positive for CD4/CD25, which indicates the presence of regulatory T cells within the lamina propria of the graft.

Figure 1 Ileal biopsy of the intestinal graft 15 years after small bowel transplantation, showing normal cytoarchitecture with long villi and well differentiated enterocytes (haematoxylin‐eosin staining, ×200). A mononuclear inflammatory infiltrate was seen within the lamina propria which was predominantly of a T cell nature (CD3, positive brown staining, ×200). Some of these cells stained positive for CD4 and CD25 (merged immunofluorescence picture resulting in a yellow colour, ×800).

To date, one can expect SB graft survival of approximately 50% five years post SBT.⁷ No follow up data are available beyond five years. Here we show for the first time that it is possible to keep a functional intestinal graft for more than 17 years, with normal life quality. The ultimate goal in transplantation medicine is the development of complete immune tolerance towards a graft, which guarantees long term survival, as recently proposed by Starzl and colleagues.¹⁰ Five rejection episodes as well as persistent inflammatory infiltrate in the graft in our patient clearly indicate lack of immune tolerance; however, the use of potent IS has allowed long term graft acceptance and function. The presence of regulatory T cells within this intestinal graft indicates some adaptive regulatory steps. Therefore, monitoring of regulatory T cells might help in elucidating the mechanisms underlying immune acceptance versus tolerance.

Acknowledgements

We would like to thank Dr Daniel Kamin, Liver, Intestine, and Multivisceral Transplant Centre, Children's Hospital Boston, Harvard University, Boston, Massachusetts, for critical reading of the manuscript. We also thank Cécile Badoual for her help with CD4‐CD25 double staining.