Biological activities of c1 inhibitor

Although T-cell mediated rejection has remained the most common form of acute rejection, humoral rejection now accounts for a substantial fraction in patients with kidney or heart allografts, and probably causes the majority of acute graft losses. The frequency, variously estimated at 20-30%, is attributed to improved methods of detection, including staining for C4d in tissues, which is more sensitive and specific than histological features. Detection of circulating anti-donor reactive antibody (usually to donor HLA antigens) confirms the diagnosis. The clinico-pathological entity of acute humoral rejection is well accepted in kidney and increasingly in heart transplantation. Recent evidence points to a new category of chronic humoral rejection, which accounts for about 60% of chronic rejection of kidneys. Importantly, the hallmark of humoral rejection, C4d, can be detected in the grafts before development of histological evidence of chronic rejection. Humoral rejection is generally not responsive to the usual anti-T cell immunosuppressive agents, but small, non-controlled trials suggest humoral rejection can be reversed with plasmapheresis, intravenous immunoglobulin, anti-CD20 and other treatments, all of which deserve formal clinical evaluation. Prophylaxis for chronic rejection is expected to require donor-specific serological monitoring and protocol biopsies.

Humoral rejection of human organ transplants.

Background

The pig-to-non-human primate model is the standard choice for in vivo studies of organ and cell xenotransplantation. In 1998, Lambrigts and his colleagues surveyed the entire world literature and reported all experimental studies in this model. With the increasing number of genetically engineered pigs that have become available during the past few years, this model is being utilized ever more frequently.



Methods

We have now reviewed the literature again and have compiled the data we have been able to find for the period January 1, 1998 to December 31, 2013, a period of 16 yr.



Results

The data are presented for transplants of the heart (heterotopic and orthotopic), kidney, liver, lung, islets, neuronal cells, hepatocytes, corneas, artery patches, and skin. Heart, kidney, and, particularly, islet xenograft survival have increased significantly since 1998.



Discussion

The reasons for this are briefly discussed. A comment on the limitations of the model has been made, particularly with regard to those that will affect progression of xenotransplantation toward the clinic.

Progress in pig-to-non-human primate transplantation models (1998-2013): a comprehensive review of the literature

Xenotransplantation: role of natural immunity.

Xenotransplantation has retained its topicality since the resurgence of interest in the mid 1990s. Work continues in many scientific fields to overcome the obstacles. However, as old problems are solved, new ones present themselves for solution. In this brief review we discuss the need for xenotransplantation, issues relating to physiological compatibilities, current ideas on how to overcome the initial aggressive hyperacute rejection (HAR) and the later immunological difficulties as well as the risks and ethical issues.

https://journals.sagepub.com/doi/pdf/10.1177/014107680309600303

Xenotransplantation: Where Are We Today?

At present, the major barrier to successful discordant xenotransplantation of unmodified or complement regulator transgenic porcine xenografts is acute vascular xenograft rejection (AVR). AVR is associated with the intragraft deposition of induced recipient xenoreactive antibodies and subsequent complement activation. In a life-supporting pig to primate kidney xenotransplantation setting using h-DAF transgenic donor organs and postoperative immunosuppression, episodes of AVR were either treated with boluses of cyclophosphamide and steroids or with the same regimen supplemented by a three-day course of C1-Inhibitor, a multifunctional complement regulator. In 8 out of 10 animals stable initial graft function was achieved; in all animals one or more episodes of AVR were observed. When, in 4 animals, C1-Inhibitor was added to the standard anti-rejection treatment regimen, AVR was successfully reversed in 6 out of 7 episodes, while in another group of 4 animals receiving the standard anti-rejection treatment 0 out of 4 episodes of AVR responded to treatment. Response to anti-rejection treatment was associated with a significant increase in recipient survival time. We conclude that AVR of h-DAF transgenic porcine kidneys can be successfully treated by additional short-term fluid phase complement inhibition.

C1-Inhibitor for treatment of acute vascular xenograft rejection in cynomolgus recipients of h-DAF transgenic porcine kidneys.

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C1-Inhibitor for treatment of acute vascular xenograft rejection in cynomolgus recipients of h-DAF transgenic porcine kidneys.