Crosstalk Between T and B Cells in the Germinal Center After Transplantation.

Crosstalk between B and T cells in transplantation is increasingly recognized as being important in the alloimmune response. T cell activation of B cells occurs by a 3-stage pathway, culminating with costimulation signals. We review the distinct T cell subtypes required for B-cell activation and discuss the formation of the germinal center (GC) after transplantation, with particular reference to the repopulation of the GC after depletional induction, and the subsequent effect of immunosuppressive manipulation of T cell-B cell interactions. In addition, ectopic GCs are seen in transplantation, but their role is not fully understood. Therapeutic options to target T cell-B cell interactions are of considerable interest, both as immunosuppressive tools, and to aid in the further understanding of these important alloimmune mechanisms.

A Complication Analysis of 2 Acellular Dermal Matrices in Prosthetic-based Breast Reconstruction.

BACKGROUND: Acellular dermal matrices (ADM) are now routine in postmastectomy prosthetic-based breast reconstruction. The goal of the current study was to compare the complications of 2 ADM products-AlloDerm and Cortiva. METHODS: A retrospective analysis of prosthetic-based breast reconstruction in Atlanta, Ga., over 5 years. Inclusion criteria were the use of the ADM types (AlloDerm or Cortiva) and use of a tissue expander or implant. Statistical analysis compared group demographics, risk factors, and early complications. RESULTS: Of the 298 breast reconstructions, 174 (58.4%) used AlloDerm and 124 (41.6%) used Cortiva. There was no difference in overall complication frequency (16 AlloDerm and 18 Cortiva; P = 0.195). Within specific categories, there was a difference in mastectomy skin flap necrosis, but, based on further regression analysis, this was attributable to differences in body mass index (P = 0.036). Furthermore, there were no differences in the rates of infection (6 AlloDerm and 5 Cortiva; P = 1.0), seroma/hematoma (9 AlloDerm and 7 Cortiva; P = 1.0), or drain duration (13.2 day AlloDerm and 14.2 day Cortiva, P = 0.2). By using a general estimating equation for binomial logistical regression, it was found that only current tobacco use (P = 0.033) was a significant predictor for a complication. Trending predictors were body mass index (P = 0.074) and age (P = 0.093). The type of matrix was not a significant predictor for any of the recorded complication (P = 0.160). CONCLUSIONS: Although AlloDerm is well established, we have shown that Cortiva has an equivalent complication frequency. Future work will focus on long-term outcome measures and histological evaluation of vascularization and integration.

Urine proteomics in kidney transplantation.

The transplanted kidney, through its urinary output, provides a medium through which the molecular constitution can provide insight into either the healthy function or developing dysfunction of a newly transplanted organ. An assay that would detect the aberration of early biomarkers of allograft injury using only urine samples from patients would provide many advantages over the current use of creatinine and tissue biopsies, as these means are either relatively non-specific or very invasive. Several urine biomarkers have been correlated with allograft injury, including CXCL9, CXCL10, CCL2, NGAL, IL-18, cystatin C, KIM-1 and Tim-3. The recent results of the CTOT-01 trial serve to validate the predictive value of the CXCL9 biomarker as a non-invasive biomarker for rejection and a prognostic indicator of graft function. There is now a preponderance of evidence showing a value of urinary monitoring of CXCL9 and CXCL10 with respect to detection of acute kidney allograft rejection. The value of the assay has been validated as a means of reducing the need for kidney transplant biopsy and applying biopsy in a more targeted manner. Additional goals for non-invasive monitoring would include predictive value prior to creatinine elevation that in turn would permit earlier, preemptive treatment of rejection.

Lymphodepletional strategies in transplantation.

Because lymphocytes were shown to mediate transplant rejection, their depletion has been studied as a mechanism of preventing rejection and perhaps inducing immunologic tolerance. Agents that profoundly deplete lymphocytes have included monoclonal antibodies, cytotoxic drugs, and radiation. We have studied several such agents but focused on antibodies that deplete not only peripheral blood lymphocytes, but also lymph node lymphocytes. Depletion of lymph node T lymphocytes appears to permit peripheral tolerance at least for T cells in animal models. Nevertheless, B-cell responses may be resistant to such approaches, and T memory cells are likewise relatively resistant to depleting antibodies. We review the experimental and clinical approaches to depletion strategies and outline some of the pitfalls of depletion, such as limitations of currently available agents, duration of tolerance, infection, and malignancy. It is notable that most tolerogenic strategies that have been attempted experimentally and clinically include depleting agents even when they are not named as the underlying strategy. Thus, there is an implicitly acknowledged role for reducing the precursor frequency of donor antigen-specific lymphocytes when approaching the daunting goal of transplant tolerance.

Post-transplant lymphoproliferative disorder associated with immunosuppressive therapy for renal transplantation in rhesus macaques (Macaca mulatta).

Human post-transplant lymphoproliferative disorder (PTLD) is an abnormal lymphoid proliferation that arises in 1-12% of transplant recipients as a consequence of prolonged immunosuppression and Epstein-Barr viral infection (EBV). Nonhuman primates, primarily rhesus macaques (Macaca mulatta), have been used extensively in research models of solid organ transplantation, as the nonhuman primate immune system closely resembles that of the human. Lymphocryptovirus of rhesus monkeys has been characterized and shown to be very similar to EBV in humans in regards to its cellular tropism, host immune response, and ability to stimulate B lymphocyte proliferation and lymphomagenesis. Thus, it appears that the NHP may be an appropriate animal model for EBV-associated lymphoma development in humans. The clinical management of post-transplant nonhuman primates that are receiving multiple immunosuppressive agents can be complicated by the risk of PTLD and other opportunistic infections. We report 3 cases of PTLD in rhesus macaques that illustrate this risk potential in the setting of potent immunosuppressive therapies for solid organ transplantation.

Tolerogenic therapies in transplantation.

Since the concept of immunologic tolerance was discovered in the 1940s, the pursuit of tolerance induction in human transplantation has led to a rapid development of pharmacologic and biologic agents. Short-term graft survival remains an all-time high, but successful withdrawal of immunosuppression to achieve operational tolerance rarely occurs outside of liver transplantation. Collaborative efforts through the NIH sponsored Immune Tolerance Network and the European Commission sponsored Reprogramming the Immune System for Establishment of Tolerance consortia have afforded researchers opportunity to evaluate the safety and efficacy of tolerogenic strategies, investigate mechanisms of tolerance, and identify molecular and genetic markers that distinguish the tolerance phenotype. In this article, we review traditional and novel approaches to inducing tolerance for organ transplantation, with an emphasis on their translation into clinical trials.

Biologics in organ transplantation.

The last two decades have witnessed a pandemic in antibody development, with over 600 entering clinical studies and a total of 28 approved by the FDA and European Union. The incorporation of biologics in transplantation has made a significant impact on allograft survival. Herein, we review the armamentarium of clinical and preclinical biologics used for organ transplantation--with the exception of belatacept--from depleting and IL-2R targeting induction agents to costimulation blockade, B-cell therapeutics, BAFF and complement inhibition, anti-adhesion, and anti-cytokine approaches. While individual agents may be insufficient for tolerance induction, they provide possibilities for reduction of steroid or calcineurin inhibitor use, alternatives to rejection episodes refractory to conventional therapies, and specialized immunosuppression for highly sensitized patients.