The immunological monitoring of alloreactive responses in liver transplant recipients: A review

Abstract

The aim of this work is to review the current knowledge in the field of immunological monitoring of allogenic responsiveness in clinical liver transplantation. When compared to other solid-organ transplants, liver allografts are considered as immunologically privileged, and, accordingly, constitute a favorable setting to develop experimental as well as clinical strategies for minimization of immunosuppression and even induction of operational tolerance. The validation of simple, reliable, noninvasive assays exploring antidonor alloreactivity will constitute a crucial step toward implementing such approaches in the clinic. In contrast to research in rodents claiming the development of donor-specific tolerance in case of graft survivals of over 100 days without immunosuppression, it is impractical to confirm tolerance induction in this way in humans. Since the first human liver transplant (LT) some 52 years ago, the vast majority of hepatic allograft recipients have remained under life-long maintenance immunosuppression (IS). Despite the dramatic improvement of early graft survival, late graft losses due to chronic rejection as well as the morbidity and mortality secondary to long-term IS remain major concerns in this field.1,2 Induction of tolerance to the transplant would prevent these complications, and clinical LT probably constitutes an ideal setting to develop such strategies, considering its immunologically privileged status when compared to other types of allografts.3 However, despite the observation that tolerance has been relatively "easy" to induce in rodent models, the translation of these researches in humans has not yet been shown to reproducibly induce IS-free tolerant state in transplant recipients. In experimental models, tolerance can be assessed by graft survival beyond 100 days without IS, and by absence of rejection of a donor strain skin transplant; such an approach is of course impractical in humans, and the only currently available method to ascertain tolerance in a given patient is the ability to progressively withdraw all IS with preservation of graft function and histology. Unfortunately, although a small number of grafts are not rejected after removal of all medications used for the maintenance IS, trials involving the deliberate withdrawal of immunosuppressive drugs according to a protocol do not suggest that it is safe to do so for most patients: Such trials are associated with the inherent risk to induce acute or even chronic rejection with the need for higher levels of IS when compared to the stable situation before attempting at IS withdrawal.

Individual Stability of Stereotypes of Immune Reacting and Modern Possibilities of Their Diagnostic in Organ Transplantation (Immune-Physiological Analysis of a Problem)

“…Между тем из-за рисков, связанных с выполнением пунк-ционной биопсии, эту манипуляцию проводят не-часто, преимущественно в диагностических целях и совсем редко в плане прогнозирования дальнейшей судьбы трансплантата (плановые исследования). Этим объясняется, что во многих случаях только резкий подъем концентрации маркерных ферментов трансплантата в крови после его пересадки служит основанием для вмешательства в текущий протокол ведения пациента [37,38].…”

“…Метод требует наличия донорских антигенов, что не составляет проблемы при пересадке органа от живого донора и требует забора и хранения до-норской крови при пересадке трупного органа [28]. Полагают, что сочетанное измерение в крови соот-ношения конкретных иммунных клеток, отражаю-щих надежность сохранения стереотипов иммун-ного статуса и показателей антигенспецифичного взаимодействия у конкретного пациента (наличие клеток памяти на аллоантигены и профиль произво-димых ими цитокинов, в частности таких, как ин-терферон гамма или интерлейкин-10), измеренные методом ELISPOT, могут дать надежный протокол конкретных действий с высокой предсказуемостью результатов и на длительные сроки [28,38,44].…”

Soluble CD30 and Acute Renal Allograft Rejection

“…After activation of CD30+ T cells, a soluble form of CD30 (sCD30) is released proteolytically, however, the biological significance of this process is still not clearly defined (Dong W. et al, 2006). Th 1 -cytokines are mainly involved in allograft rejection, while Th2-type immune response may be graft protective by blocking the graft damaging Th1-type anti-donor response (Reding R. et al, 2006). A soluble form of CD30 (sCD30) is released into the bloodstream after activation of CD30+ T cells (Romagnani S. et al, 1995).…”

Increased CD64 expression on polymorphonuclear neutrophils indicates infectious complications following solid organ transplantation

“…Recently, several trials showed potentially valuable conventional markers (ALT, cholesterol, prothrombin time, soluble IL-2R) (7,8) and cellular markers (eosinophils, lymphocytes) for diagnosing rejection. In particular, the identification and diagnostic use of T cell subtypes is currently a widely discussed approach (7,9,10,11). In clinical practice, a combination of broad panels is necessary to determine complications (7,8).…”

“…Other investigated ways for the recognition of rejection crisis are the detection of anti-HLA antibodies or soluble CD30 (9,11,(12)(13)(14), as well as the detection of the complement split product C4d (15) or monitoring Neopterin (16) or gamma glutamyl transferase (17). Additional explored ways of postoperative transplant monitoring are the sequential monitoring of peripheral blood mononuclear cells (PBMC) to detect changed chemokine receptor/ligand gene expression (18)(19)(20) and the measurement of urinary mRNA expression of various immune molecules (21).…”