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With the success of solid organ transplantation has come the realization of the post-transplant morbidity and mortality related to the use of immunosuppressive medications (1–3). Induction of tolerance to the transplanted organ would likely prevent these complications, however, the use of tolerance induction protocols in solid organ transplantation will require assays that reflect the level of immune alloreactivity (allosensitization) of the recipient towards the donor. In order to understand the basis of in vitro assays of allosensitization, several concepts have to be considered. The dominant form of alloantigen is the non-self HLA molecule complexed with a variety of different peptides in its antigen binding groove. The frequency of precursor cells for an alloresponse is thought to be 100–1000 times as strong as the response to standard non-self antigens (4). Additionally, the alloresponse, unlike the response to most other antigens, is not dependent on previous exposure for an initial immune response (4). Any strategies to prevent allorecognition must take into account these cardinal observations. For the immune system to mount a response against a foreign antigen, it must be aware of the antigen’s presence. T cells recognize alloantigen via both direct and indirect pathways (Fig. 1) (5). In the direct pathway, recipient T cells recognize intact donor MHC alloantigens on the surface of donor-derived APC. Acute allograft rejection is thought to be mediated predominantly via this pathway (6). In the indirect pathway, allogeneic MHC molecules shed from the graft are processed by the recipient APC and then presented as peptides within the peptide binding sites of the recipient’s own MHC molecules. There is ample evidence that indirect allorecognition is an important driver of organ transplant rejection in humans (7–10). One of the challenges with measuring responses mediated by the indirect pathway is the low precursor frequency of indirectly primed T cells (6) compared to directly primed cells. Fig. 1 Two mechanisms for allorecognition. Direct allorecognition involves recognition of foreign HLA with a variety of potential peptides present in the antigen-presentation groove. In contrast, indirect allorecognition involves recognition of specific foreign ... This review will summarize in vitro assays of T cell reactivity that reflect alloantigen-specific responses. Humoral issues, proteomics, and genomics will not be covered in this review.

Neonatal hemochromatosis (NH) is a rare disease of gestation that results in fetal liver injury and extrahepatic siderosis. The etiology of NH is not fully understood. However, the rate of recurrence of NH in the pregnancy after an affected one is ∼80%. A spectrum of liver disease has been recognized, spanning from liver failure in the fetus or neonate to infants that survive with medical therapy. Here we report on 2 sets of fraternal twins, each set with a gross disparity in the severity of presentation: 1 infant with liver failure and the other nearly unaffected. These findings suggest a need to look carefully for subclinical disease in the siblings of patients with NH by using sensitive tests such as those for ferritin and α-fetoprotein. They also suggest that affected infants may be missed when using routine clinical testing, which would lead to the apparent rate of recurrence, understating the actual recurrence rate.