Liver transplantation has become standard practice for treating end-stage liver disease. The success of the procedure relies on effective immunosuppressive medications to control the host's immune response. Despite the liver's inherent capacity to foster tolerance, the early post-transplant period is marked by significant immune reactivity. To ensure favorable outcomes, it is imperative to identify and manage various rejection types, encompassing T-cell-mediated, antibody-mediated, and chronic rejection. However, the approach to prescribing immunosuppressants relies heavily on clinical judgment rather than evidence-based criteria. Given that the majority of patients will require lifelong immuno suppression as the mechanisms underlying operational tolerance are still being investigated, healthcare providers must possess an understanding of immune responses, rejection mechanisms, and the pathways targeted by immunosuppressive drugs. This knowledge enables customization of treatments and improved patient care, even though a consensus on an optimal immunosuppressive regimen remains elusive.

The neonatal fragment crystallizable (Fc) receptor (FcRn) functions as a recycling mechanism to prevent degradation and extend the half-life of IgG and albumin in the circulation. Several FcRn inhibitors selectively targeting IgG recycling are now moving rapidly toward clinical practice in neurology and hematology. These molecules accelerate the destruction of IgG, reducing pathogenic IgG and IgG immune complexes, with no anticipated effects on IgA, IgM, IgE, complement, plasma cells, B cells, or other cells of the innate or adaptive immune systems. FcRn inhibitors have potential for future use in a much wider variety of antibody-mediated autoimmune diseases. Given the imminent clinical use, potential for broader utility, and novel mechanism of action of FcRn inhibitors, here we review data from 4 main sources: (a) currently available activity, safety, and mechanism-of-action data from clinical trials of FcRn inhibitors; (b) other procedures and treatments that also remove IgG (plasma donation, plasma exchange, immunoadsorption); (c) diseases resulting in loss of IgG; and (d) primary immunodeficiencies with potential mechanistic similarities to those induced by FcRn inhibitors. These data have been evaluated to provide practical considerations for the assessment, monitoring, and reduction of any potential infection risk associated with FcRn inhibition, in addition to highlighting areas for future research.

Immunosuppressive therapy greatly contributed to making liver transplantation the standard treatment for end-stage liver diseases. However, it remains difficult to predict and measure the efficacy of pharmacological immunosuppression. Therefore, we used a panel of standardized, commonly available, biomarkers with the aim to describe their changes in the first 3 weeks after the transplant procedure and assess if they may help therapeutic drug monitoring in better tailoring the dose of the immunosuppressive drugs. We prospectively studied 72 consecutive patients from the day of liver transplant (post-operative day #0) until the post-operative day #21. Leukocytes, neutrophils, lymphocytes (CD4+, CD8+), natural killer cells, monocytes, immunoglobulins and tacrolimus serum levels were measured on peripheral blood (at day 0, 3, 7, 14, 21 after surgery). Patients who developed infections showed significantly higher CD64+ monocytes on post operative day #7. IgG levels were lower on post operative day #3 among patients who later developed infections. We also found that a sharp decrease in IgA from post operative day #0 to 3 (-226 mg/dL in the ROC curve analysis) strongly correlates with the onset of infections among HCV- patients. No specific markers of rejection emerged from the tested panel of markers. Our results show that some early changes in peripheral blood white cells and immunoglobulins may predict the onset of infections and may be useful in modulating the immunosuppressive therapy. However, a panel of commonly available, standardized biomarkers do not support in improving therapeutic drug monitoring ability to individualize immunosuppressive drugs dosing.

Chronic rejection affects the long-term survival of all solid organ transplants and, among intestinal allografts, occurs in up to 10% of the recipients. The insidious clinical evolution of the chronic allograft enteropathy, the absence of noninvasive biomarkers, and the late endoscopic findings delay its diagnosis. No pharmacological approach has been proven effective, and allograft removal nowadays still represents the only available therapy. The inclusion of the liver in the visceral allograft appears to be the only intervention affecting the development of chronic rejection, as revealed by large-center studies and registry reports. A significant body of evidence emerged from the experimental setting and provided essential knowledge on the complex mechanisms behind the development of chronic allograft enteropathy. More recently, donor-specific antibodies have been suggested as an early, key element in the natural history of chronic allograft enteropathy and several novel approaches, tackling the antibody-mediated graft injury, have gained acceptance in clinical settings and are believed to impact on chronic rejection. The inclusion of a liver allograft is advocated when re-transplanting a sensitized recipient, due to its protective effect against humoral immunity. Multicenter trials are required to understand and tackle chronic rejection, and find the therapeutic answer to this clinical dilemma.

Severe hypogammaglobulinemia (HGG) (IgG <400 mg/dL) following intestinal transplantation is common. Although IgG replacement therapy is commonly used, clinical outcomes associated with increasing IgG levels to >400 mg/dL are not well described.

Kaplan-Meier analysis was performed to estimate survival, the log-rank test to compare survival distributions between groups, and the Fisher exact test to determine the association between HGG and rejection.

A total of 23 intestinal transplant (IT) recipients with a median age of 2.3 years (range, 0.7-41 years) at the time of HGG diagnosis were included. The types of transplants were liver-small bowel (73.9%), liver-small bowel-kidney (8.7%), and small bowel only (17.4%). The 3-year survival after the diagnosis of HGG was 50.2% (95% confidence interval [CI] = 28.2%-68.7%). There was no difference in survival (P = .67) when patients were dichotomized based upon IgG level at last follow-up (IgG ≥400 mg/dL, n = 14; and IgG <400 mg/dL, n = 9). There was no also evidence of an association between survival and: total dose (P = .58), frequency (P = .11), and number of IgG doses administered (P = .8). There was no difference in survival between patients receiving (n = 12) or not receiving (n = 11) cytomegalovirus hyperimmunoglobulin (P = .10).

Improved survival rates were not found in our IT recipients with severe HGG with immunoglobulin therapy to IgG levels of ≥400 mg/dL, even when cytomegalovirus hyperimmunoglobulin was administered.

New biomarkers are necessary to improve detection of the risk of infection in heart transplantation. We performed a multicenter study to evaluate humoral immunity profiles that could better enable us to identify heart recipients at risk of severe infections.

We prospectively analyzed 170 adult heart recipients at 8 centers in Spain. Study points were before transplantation and 7 and 30 days after transplantation. Immune parameters included IgG, IgM, IgA and complement factors C3 and C4, and titers of specific antibody to pneumococcal polysaccharide antigens (anti-PPS) and to cytomegalovirus (CMV). To evaluate potential immunologic mechanisms leading to IgG hypogammaglobulinemia, before heart transplantation we assessed serum B-cell activating factor (BAFF) levels using enzyme-linked immunoassay. The clinical follow-up period lasted 6 months. Clinical outcome was need for intravenous anti-microbials for therapy of infection.

During follow-up, 53 patients (31.2%) developed at least 1 severe infection. We confirmed that IgG hypogammaglobulinemia at Day 7 (defined as IgG <600 mg/dl) is a risk factor for infection in general, bacterial infections in particular, and CMV disease. At Day 7 after transplantation, the combination of IgG <600 mg/dl + C3 <80 mg/dl was more strongly associated with the outcome (adjusted odds ratio 7.40; 95% confidence interval 1.48 to 37.03; p = 0.014). We found that quantification of anti-CMV antibody titers and lower anti-PPS antibody concentrations were independent predictors of CMV disease and bacterial infections, respectively. Higher pre-transplant BAFF levels were a risk factor of acute cellular rejection.

Early immunologic monitoring of humoral immunity profiles proved useful for the identification of heart recipients who are at risk of severe infection.

Intestinal failure and associated parenteral nutrition-induced liver failure cause significant morbidity, mortality, and health care burden. Intestine transplantation is now considered to be the standard of care in patients with intestinal failure who fail intestinal rehabilitation. Intestinal failure-associated liver disease is an important sequela of intestinal failure, caused by parenteral lipids, requiring simultaneous liver-intestine transplant. Lipid minimization and, in recent years, the emergence of fish oil-based lipid emulsions have been shown to reverse parenteral nutrition-associated hyperbilirubinemia, but not fibrosis. Significant progress in surgical techniques and immunosuppression has led to improved outcomes after intestine transplantation. Intestine in varying combination with liver, stomach, and pancreas, also referred to as multivisceral transplantation, is performed for patients with intestinal failure along with liver disease, surgical abdominal catastrophes, neuroendocrine and slow-growing tumors, and complete portomesenteric thrombosis with cirrhosis of the liver. Although acute and chronic rejection are major problems, long-term survivors have excellent quality of life and remain free of parenteral nutrition.

Severe hypogammaglobulinemia (IgG < 400 mg/dL) has adverse impact on mortality during the first year post-transplantation. The aim of the study was to determine whether increasing IgG levels to ≥400 mg/dL improved outcomes.

Kaplan-Meier analyses were performed to estimate survival, log-rank test to compare survival distributions between groups, and Fisher's exact test to determine the association between hypogammaglobulinemia and rejection or graft loss.

Thirty-seven solid organ transplant (SOT) recipients were included. Hypogammaglobulinemia was diagnosed at median of 5.6 months (range: 0-291.8 months) post-transplantation. Types of transplants: liver-small bowel (17); liver-small bowel-kidney (2); liver (5); small bowel (4); liver-kidney (1); kidney/kidney-pancreas (3); heart (3); heart-kidney (1); and heart-lung (1). The three-yr survival after the diagnosis of hypogammaglobulinemia was 49.5% (95% CI: 32.2-64.6%). Patients were dichotomized based upon IgG level at last follow-up: IgG ≥ 400 mg/dL (23 patients) and IgG < 400 mg/dL (14 patients). There was no evidence of a difference in survival (p = 0.44), rejection rate (p = 0.44), and graft loss censored for death (p = 0.99) at one yr between these two groups. There was no difference in survival between patients receiving or not immunoglobulin (p = 0.99) or cytomegalovirus hyperimmunoglobulin (p = 0.14).

Severe hypogammaglobulinemia after SOT is associated with high mortality rates, but increasing IgG levels to ≥400 mg/dL did not seem to translate in better patient or graft survival in this cohort.

Infectious complications remain a leading cause of morbidity and mortality after solid organ transplantation (SOT), and largely depend on the net state of immunosuppression achieved with current regimens. Cytomegalovirus (CMV) is a major opportunistic viral pathogen in this setting. The application of strategies of immunological monitoring in SOT recipients would allow tailoring of immunosuppression and prophylaxis practices according to the individual's actual risk of infection. Immune monitoring may be pathogen-specific or nonspecific. Nonspecific immune monitoring may rely on either the quantification of peripheral blood biomarkers that reflect the status of a given arm of the immune response (serum immunoglobulins and complement factors, lymphocyte sub-populations, soluble form of CD30), or on the functional assessment of T-cell responsiveness (release of intracellular adenosine triphosphate following a mitogenic stimulus). In addition, various methods are currently available for monitoring pathogen-specific responses, such as CMV-specific T-cell-mediated immune response, based on interferon-γ release assays, intracellular cytokine staining or main histocompatibility complex-tetramer technology. This review summarizes the clinical evidence to date supporting the use of these approaches to the post-transplant immune status, as well as their potential limitations. Intervention studies based on validated strategies for immune monitoring still need to be performed.