Rita Bottino

• Professor (Associate) at Allegheny General Hospital

Pig islet xenotransplantation in nonhuman primates (NHPs) has made considerable progress during the past 30 years, and European scientists in both Europe and the USA have contributed to this progress. At times, there have been, or are, active research programs in Sweden, Germany, Belgium, and the USA. The first clinical experiments of wild-type (i....

Porcine kidney xenotransplantation for end‐stage renal disease (ESRD) has reached the stage of clinical testing following major advances in donor pig genetic modifications and effective immunosuppressive strategies through decades of rigorous translational research. Reports of pig kidney xenograft survival beyond 1 year posttranplant in nonhuman pr...

Porcine kidney xenotransplantation for end-stage renal disease (ESRD) has reached the stage of clinical testing following major advances in donor pig genetic modifications and effective immunosuppressive strategies through decades of rigorous translational research. Reports of pig kidney xenograft survival beyond 1 year post-transplant in nonhuman...

Recent landmark clinical translation of xenotransplantation depended upon multiple innovations by the xenotransplant community, including the introduction of a variety of source pig genetic modifications, technical innovations, and novel immunosuppressive strategies, as well as the development of ethical and regulatory frameworks to support transla...

Recent landmark clinical translation of xenotransplantation depended upon multiple innovations by the xenotransplant community, including the introduction of a variety of source pig genetic modifications, technical innovations, and novel immunosuppressive strategies, as well as the development of ethical and regulatory frameworks to support transla...

Human endocrine cell differentiation and islet morphogenesis play critical roles in determining islet cell mass and function, but the events and timeline of these processes are incompletely defined. To better understand early human islet cell development and maturation, we collected 115 pediatric pancreata and mapped morphological and spatiotempora...

Proliferative quiescence in β-cells is required to maintain functional competence. While this presents a significant hurdle in regenerative therapy for diabetes, the molecular underpinnings of this reciprocal relationship remain unclear. Here, we demonstrate that TEAD1, the transcription effector of the mammalian-Hippo pathway, drives developmental...

Proliferative quiescence in β-cells is required to maintain functional competence. While this presents a significant hurdle in regenerative therapy for diabetes, the molecular underpinnings of this reciprocal relationship remain unclear. Here, we demonstrate that TEAD1, the transcription effector of the mammalian-Hippo pathway, drives developmental...

Type 2 diabetes mellitus (T2D), a major cause of worldwide morbidity and mortality, is characterized by dysfunction of insulin-producing pancreatic islet β cells1,2. T2D genome-wide association studies (GWAS) have identified hundreds of signals in non-coding and β cell regulatory genomic regions, but deciphering their biological mechanisms remains...

The endocrine and exocrine compartments of the pancreas are spatially related but functionally distinct. Multiple diseases affect both compartments, including type 1 diabetes (T1D), pancreatitis, cystic fibrosis, and pancreatic cancer. To better understand how the exocrine pancreas changes with age, obesity, and diabetes, we performed a systematic...

Objective: There is an urgent need for safe and targeted interventions to mitigate post-ERCP pancreatitis (PEP). Calcineurin inhibitors (CnIs) offer therapeutic promise as calcineurin signaling within acinar cells is a key initiating event in PEP. In previous proof-of-concept studies using experimental models, we showed that concurrent intra-pancr...

Defining the neurovascular architecture in the pancreas of individuals with type 1 diabetes (T1D) is crucial to understanding the mechanisms of dysregulated glucagon secretion. In the largest T1D cohort of biobanked tissues analyzed to date, we found that pancreatic capillaries and nerve fibers persist in human T1D despite beta cell loss, suggestin...

Objective Total pancreatectomy with islet autotransplantation (TPIAT) is a definitive management for intractable pain in patients with chronic pancreatitis. Islet autotransplantation (IAT) allows for the preservation of beta-cells to prevent complications of long-term diabetes. Our study follows TPIAT recipients for up to 12 years to determine the...

Bromocriptine is approved as a diabetes therapy, yet its therapeutic mechanisms remain unclear. Though bromocriptine’s actions have been mainly attributed to stimulation of brain dopamine D2 receptors (D2R), bromocriptine also targets the pancreas. Here, we employ bromocriptine as a tool to elucidate roles of catecholamine signaling in regulating p...

Dopaminergic agonism effectively treats dysglycemia, with dopaminergic agonist bromocriptine approved as a type 2 diabetes therapy. Though bromocriptine’s actions have been mainly attributed to stimulation of dopamine D2 receptors (D2R) in the brain, we previously showed that bromocriptine also targets metabolically-relevant peripheral tissues incl...

Type 2 diabetes (T2D) is associated with increased risk of pancreatic cancer. Our knowledge of exocrine pancreas histopathology in T2D is incomplete. To determine whether T2D is associated with changes in the pancreatic exocrine compartment, we analyzed tissue sections from the pancreatic head, body, and tail of 25 T2D donors (age 51 ± yrs, duratio...

Patient: Female, 51-year-old Final Diagnosis: Idiopathic chronic pancreatitis Symptoms: Poor pain control Medication: — Clinical Procedure: TPAIT Specialty: Endocrinology and Metabolic Objective Unknown etiology Background SARS-CoV-2 infection or COVID-19 disease has been linked to the onset of diabetes and metabolic dysregulation because it has...

Islet cell transplantation can successfully restore endogenous insulin production in patients with type 1 diabetes; however, like whole organ transplantation it is limited by human organ (pancreas) donation. Islet xenotransplantation has been proposed as a means to overcome this limitation. Pigs are considered to be an ideal replacement source of i...

A hallmark of type 2 diabetes (T2D), a major cause of world-wide morbidity and mortality, is dysfunction of insulin-producing pancreatic islet β cells. T2D genome-wide association studies (GWAS) have identified hundreds of signals, mostly in the non-coding genome and overlapping β cell regulatory elements, but translating these into biological mech...

The inflammatory response is an obstacle to success in both allogeneic and autologous islet transplantation. In autologous islet transplantation (AIT), however, the recipient is also the donor, permitting pretreatment of donor/recipient for a controlled duration prior to transplantation. We sought to exploit this feature of (AIT) by pretreating don...

Clinical and pathologic heterogeneity in type 1 diabetes is increasingly being recognized. Findings in the islets and pancreas of a 22-year-old male with 8 years of type 1 diabetes were discordant with expected results and clinical history (islet autoantibodies negative, A1C 11.9%) and led to comprehensive investigation to define the functional, mo...

Chronic pancreatitis (CP) is a complex inflammatory disorder with numerous associated genetic and environmental risk factors. The most distressing characteristic of CP is recalcitrant pain, often requiring surgical resection including total pancreatectomy with islet autotransplantation (TPIAT). We studied 5 consented subjects undergoing pancreatic...

Islet-enriched transcription factors (TFs) exert broad control over cellular processes in pancreatic α and β cells and changes in their expression are associated with developmental state and diabetes. However, the implications of heterogeneity in TF expression across islet cell populations are not well understood. To define this TF heterogeneity an...

Objectives: Islet cultures are routinely performed in total pancreatectomy with islet autotransplantation (TPIAT), and the need for empiric antibiotic treatment based on culture results is unknown. We evaluated the effect of postoperative antibiotic treatment for positive islet cultures on clinical infection. Methods: Seventy-nine patients under...

Procuring and preparing human pancreas for paraffin-embedding, fixed cryosections, flash frozen sections, and RNA isolation. This protocol was developed in collaboration with Dr. Rita Bottino of Imagine Pharma and Allegheny Health Network and is based on protocols developed by Dr. Marcela Brissova of Vanderbilt University.

Context: Total pancreatectomy (TP) with islet-cell auto transplantation (IAT) is an option for pain management for patients with chronic pancreatitis (CP). IAT allows the preservation of beta cell function to reduce or prevent long-term diabetes. Objective: We performed a follow-up study up to 12 years after TPIAT surgery with an off-site isolation...

Islet transplantation can restore glycemic control in patients with type 1 diabetes. Using this procedure, the early stages of engraftment are often crucial to long-term islet function, and outcomes are not always successful. Numerous studies have shown that mesenchymal stem cells (MSCs) facilitate islet graft function. However, experimental data c...

Clinical islet transplantation was first realized over four decades ago at the University of Minnesota. Autologous islet transplantation is now widely recognized as a treatment to prevent diabetes in patients after pancreas excision and is offered at major transplant centers throughout the United States and the world. Type 1 diabetes represents a m...

Islet-enriched transcription factors (TFs) exert broad control over cellular processes in pancreatic α and β cells and changes in their expression are associated with developmental state and diabetes. However, the implications of heterogeneity in TF expression across islet cell populations are not well understood. To define this TF heterogeneity an...

Dopamine (DA) and norepinephrine (NE) are catecholamines primarily studied in the central nervous system that also act in the pancreas as peripheral regulators of metabolism. Pancreatic catecholamine signaling has also been increasingly implicated as a mechanism responsible for the metabolic disturbances produced by antipsychotic drugs (APDs). Crit...

Background: Type 1 diabetes (T1DM) is a chronic autoimmune disease characterized by T-cell-mediated destruction of insulin-producing beta cells. Evidence shows that patients with T1DM and mice used in specific diabetic models both exhibit changes in their intestinal microbiota and dysregulated microbiota contributes to the pathogenesis of T1DM. Is...

ACE2 and TMPRSS2 mRNA are expressed in the human pancreas d ACE2 protein is expressed in some islet and exocrine capillaries and pericytes d ACE2 and TMPRSS2 proteins are co-expressed in some pancreatic ducts d ACE2 and TMPRSS2 protein is not detected in b cells of the human pancreas. In Brief Coate et al. examined expression of canonical SARS-CoV-...

Background & aims: Molecular evidence of cellular heterogeneity in the human exocrine pancreas has not been yet established because of the local concentration and cascade of hydrolytic enzymes that can rapidly degrade cells and RNA upon pancreatic resection. We sought to better understand the heterogeneity and cellular composition of the pancreas...

Cytokine induced β-cell apoptosis is the major pathogenic mechanism in type 1 diabetes (T1D). Despite significant advances in understanding underlying mechanisms, few drugs have been translated to protect β-cells in T1D. Epigenetic modulators such as bromodomain-containing BET (Bromo- and Extra-Terminal) proteins are important regulators of immune...

The immunologic barriers to successful xenotransplantation are related to the presence of natural anti-pig antibodies in humans and nonhuman primates that bind to antigens expressed on the transplanted pig organ (the most important of which is galactose-α1,3-galactose [Gal]) and activate the complement cascade, which results in rapid destruction of...

Many patients who would undergo organ transplantation cannot proceed due to the inability of human organ donation to satisfy medical needs. Xenotransplantation has the potential to offer unlimited availability of pig organs for transplantation, and pig‐to‐non‐human primate models have demonstrated outcomes that may soon justify clinical trials. How...

Selective inhibitors of sodium glucose cotransporter-2 (SGLT2) are widely used for the treatment of type 2 diabetes (T2D) and act primarily to lower blood glucose by preventing glucose reabsorption in the kidney. However, it is controversial whether these agents also act on the pancreatic islet, specifically the α cell, to increase glucagon secreti...

Aims/hypothesis: Individuals with longstanding and recent-onset type 1 diabetes have a smaller pancreas. Since beta cells represent a very small portion of the pancreas, the loss of pancreas volume in diabetes is primarily due to the loss of pancreatic exocrine mass. However, the structural changes in the exocrine pancreas in diabetes are not well...

Pancreatic islets secrete insulin from β cells and glucagon from α cells and dysregulated secretion of these hormones is a central component of diabetes. Thus, an improved understanding of the pathways governing coordinated β and α cell hormone secretion will provide insight into islet dysfunction in diabetes. However, the three-dimensional multice...

Diabetes ensues when there is a net decrease in functional β-cell mass. Efforts to increase β-cell mass are limited by a concurrent loss of mature function. The molecular mechanisms underlying the reciprocal regulation between β-cell proliferation and mature function are unclear. Here, we demonstrate that constitutive and inducible genetic deletion...

The advancement toward a clinical application for porcine islets to cure diabetes in humans must include reproducible long-term successes in non-human primate (NHP) models. Many dedicated researchers around the world are continuing to work toward this goal. In this chapter, we describe procedures for islet isolation of pancreatic islets from adult...

Posttransplantation diabetes mellitus (PTDM) is a common and significant complication related to immunosuppressive agents required to prevent organ or cell transplant rejection. To elucidate the effects of 2 commonly used agents, the calcineurin inhibitor tacrolimus (TAC) and the mTOR inhibitor sirolimus (SIR), on islet function and test whether th...

G-protein-coupled-receptors (GPCRs) modulate insulin secretion from β cells and glucagon secretion from α cells. Here, we developed an integrated approach to study the function of primary human islet cells using genetically modified pseudoislets that resemble native islets across multiple parameters. We studied the Gi and Gq GPCR pathways by expres...

The cellular heterogeneity of the human pancreas has not been previously characterized due to the presence of extreme digestive enzymatic activities, causing rapid degradation of cells and RNA upon resection. Therefore, previous cellular mapping studies based on gene expression were focused on pancreatic islets, leading to a vast underrepresentatio...

Asparaginase (ASNase) causes pancreatitis in approximately 10% of leukemia patients, and the mechanisms underlying this painful complication are not known. ASNase primarily depletes circulating asparagine, and the endogenously expressed enzyme, asparagine synthetase (ASNS), replenishes asparagine. ASNS was suggested previously to be highly expresse...

Reliance on rodents for understanding pancreatic genetics, development and islet function could limit progress in developing interventions for human diseases like diabetes mellitus. Similarities of pancreas morphology and function suggest that porcine and human pancreas developmental biology may have useful homologies. However, little is known abou...

It can reasonably be anticipated that, within 5-10 years, islet allotransplantation or pig islet xenotransplantation may be the preferred options for β-cell replacement therapy. The portal vein/liver is currently the preferred clinical site for free islet transplantation, constituting 90% of clinical islet transplants. Despite being the site of cho...

Rationale: Although autologous islet transplantation aims to prevent surgically-induced insulin-dependent diabetes in patients undergoing total pancreatectomy, only approximately one third of patients achieve insulin independence. To test the hypothesis that reducing nonspecific inflammation improves graft function post-AIT, we conducted a pilot cl...

Individuals with longstanding type 1 diabetes (T1D) have smaller pancreata. Recent studies have found that pancreas volume is less at the time of T1D diagnosis and slightly decreased in auto-antibody positive, nondiabetic (ND) individuals. The reduced pancreas size in T1D cannot be due solely to β cell loss, since islets make up only ~2% of total p...

Impaired counterregulatory response of glucagon to hypoglycemia is a common complication of type 1 diabetes (T1D). One proposed contributor to abnormal glucagon secretion is decreased sympathetic innervation in T1D islets. To systematically assess the innervation of human pancreatic tissues, we examined samples from donors with recent-onset T1D (<1...

Objectives: Autologous islet transplantation (AIT) is performed to preserve insulin secretory function in chronic pancreatitis patients undergoing total pancreatectomy (TP). No data exist on the effect of time lapse on beta cell function post TP-AIT. We aimed to investigate the factor of time lapse on beta cell function following TP-AIT. Methods:...

Background: Islet transplantation has progressively become a safe alternative to pancreas transplantation for the treatment of type 1 diabetes. However, the long-term results of islet transplantation could be significantly increased by improving the quality of the islet isolation technique even exploring alternative islet transplantation sites to...

Pancreatic islet allotransplantation is a treatment for patients with severe forms of type 1 diabetes. As long‐term graft function and survival are not yet optimal, additional studies are warranted in order to continue improving transplant outcomes. The mechanisms of islet graft loss and tolerance induction are often studied in murine diabetes mode...

Type 1 diabetes studies consistently generate data showing islet β-cell dysfunction and T cell-mediated anti-β-cell-specific autoimmunity. To explore the pathogenesis, we interrogated the β-cell transcriptomes from donors with and without type 1 diabetes using both bulk-sorted and single β-cells. Consistent with immunohistological studies, β-cells...

The cover image is based on the Meeting Report Third WHO Global Consultation on Regulatory Requirements for Xenotransplantation Clinical Trials,Changsha, Hunan, China 12 ‐ 14 December, 2018 by Wayne J. Hawthorne et al., DOI: 10.1111/xen.12513

Islet transplantation has been proposed to be a potential treatment for type 1 diabetes. Recent compelling evidence indicates that intravascular islet infusion is far from ideal and therefore, the omentum is re-emerging as a potentially valuable site for islet transplantation. This experiment requires the isolation of high quality islets and the im...

Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found that donor islets contained β cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings...

Developing systems to identify the cell type-specific functions regulated by genes linked to type 2 diabetes (T2D) risk could transform our understanding of the genetic basis of this disease. However, in vivo systems for efficiently discovering T2D risk gene functions relevant to human cells are currently lacking. Here we describe powerful interdis...

Understanding the genomic logic that underlies cellular diversity and developmental potential in the human pancreas will accelerate the growth of cell replacement therapies and reveal genetic risk mechanisms in diabetes. Here, we identified and characterized thousands of chromatin regions governing cell-specific gene regulation in human pancreatic...

Milestones in the history of diabetes therapy include the discovery of insulin and successful methods of beta cell replacement including whole pancreas and islet cell transplantation options. While pancreas transplantation remains the gold standard for patients who have difficulty controlling their symptoms with exogenous insulin, islet allotranspl...

Total pancreatectomy (TP) is increasingly being utilized for definitive treatment in patients with debilitating chronic pancreatitis (CP). In an effort to prevent surgical diabetes, the procedure can be performed in conjunction with transplantation of islets of Langerhans recovered from the patients' own resected pancreas (autologous islet transpla...

IMG-1 is a novel therapeutic for the treatment of types 1 and 2 diabetes that may have islet regenerative properties. 300 islets isolated from mouse pancreases were cultured in standard media with IMG-1 (0.5µg/mL) and compared with control non-treatment. Within 24 hours, the IMG-1 treated islets became smaller (less clustered) and islet cells appea...

Dapagliflozin (DAPA), a selective Sodium Glucose Cotransporter-2 (SGLT2) inhibitor, is widely used for the treatment of type 2 diabetes (T2D). In T2D individuals, DAPA increases plasma glucagon, decreases insulin secretion, and improves muscle insulin sensitivity. DAPA has been reported to increase glucagon secretion in cultured normal human islets...

T2D is characterized by progressive pancreatic islet dysfunction; however, dissecting causes of this dysfunction in humans is challenging due to disease heterogeneity and the difficulty of obtaining relevant pancreatic samples. To address these challenges, we used an integrated approach to functionally and molecularly study the native pancreas and...

The Developmental Origins of Health and Disease Hypothesis states that the in utero environment influences postnatal health and plays a role in disease etiology. In humans, exposure to maternal obesity in utero increases diabetes susceptibility in the offspring. In the U.S., it is estimated that about half of pregnancies occur in overweight or obes...

Cystic fibrosis-related (CF-related) diabetes (CFRD) is an increasingly common and devastating comorbidity of CF, affecting approximately 35% of adults with CF. However, the underlying causes of CFRD are unclear. Here, we examined cystic fibrosis transmembrane conductance regulator (CFTR) islet expression and whether the CFTR participates in islet...

In spite of tolerance mechanisms, some individuals develop T cell mediated autoimmunity. Post-translational modifications that increase the affinity of epitope presentation and/or recognition represent one means through which self-tolerance mechanisms can be circumvented. We investigated T cell recognition of peptides that correspond to modified be...

Chronic pancreatitis (CP) is a severely disabling disorder with potential detrimental effects on quality of life, gut function, and glucose homeostasis. Disease progression often results in irreversible morphological and functional abnormalities with development of chronic pain, mechanical obstruction, and pancreatic insufficiency. Along with compr...

Many patients with type 1 diabetes (T1D) have residual β cells producing small amounts of C-peptide long after disease onset but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features of these residual β cells and α cells in the islet endocrine compartment are largely unknown, due to the difficulty of comprehe...

Inadequate pancreatic β cell function underlies type 1 and type 2 diabetes mellitus. Strategies to expand functional cells have focused on discovering and controlling mechanisms that limit the proliferation of human β cells. Here, we developed an engraftment strategy to examine age-associated human islet cell replication competence and reveal mecha...

As organisms age, cells accumulate genetic and epigenetic errors that eventually lead to impaired organ function or catastrophic transformation such as cancer. Because aging reflects a stochastic process of increasing disorder, cells in an organ will be individually affected in different ways, thus rendering bulk analyses of postmitotic adult cells...

Islet allotransplantation results in increasing success in treating type 1 diabetes, but the shortage of deceased humandonor pancreata limits progress. Islet xenotransplantation, using pigs as sources of islet is a promising approach to overcome this limitation. The greatest obstacle is the primate immune/ inflammatory response to the pig islets, w...

Type 1 diabetes (T1D) is an autoimmune disease characterized by the infiltration of lymphocytes into the insulin-producing β-cells in the pancreas. We have isolated live T cells sorted or grown directly from the isolated, handpicked islets of human donors with T1D. We received ~500 islet equivalent EQ of variable purity (10-90%) from 12 donors with...

As organisms age, cells accumulate genetic and epigenetic changes that eventually lead to impaired organ function or catastrophic transformation such as cancer. Since aging appears to be a stochastic process of increasing disorder ¹ cells in an organ will be individually affected in different ways - thus rendering bulk analyses of postmitotic adult...

In the version of this article initially published online, the authors forgot to acknowledge the islet-isolation team at the Diabetes Research Institute, University of Miami. This oversight has been corrected for the print, PDF and HTML versions of this article. © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.

Anti-CD154mAb is a powerful co-stimulation blockade agent that is efficacious in preventing rejection, even in xenogeneic settings. It has been used in the majority of successful long-term pig-to-non-human primate islet transplantation models. However, its clinical use was halted as a result of thromboembolic complications that were also observed i...

Context: Spontaneous hypoglycemia has been reported in patients following total pancreatectomy (TP) and islet autotransplantation (IAT) with maintained insulin independence. Details surrounding these events have not been well described. Objective: To determine the frequency and characteristics of spontaneous hypoglycemia in patients undergoing TP-I...

With the encouraging results of pancreatic islet allotransplantation, increasing attention is being directed towards pig islet xenotransplantation, which would resolve the problem of islet supply (Markmann et al., 2016, Ekser et al., 2012). Free (nonencapsulated) pig islets (either wild-type or genetically-engineered) have maintained normoglycemia...

Selection of an optimal donor pancreas is the first key task for successful islet isolation. We conducted a retrospective multicenter study in 11 centers in North America to develop an islet donor scoring system using donor variables. The data set consisting of 1,056 deceased donors was used for development of scoring system to predict islet isolat...

Intensive efforts are focused on identifying regulators of human pancreatic islet cell growth and maturation to accelerate development of therapies for diabetes. After birth, islet cell growth and function are dynamically regulated; however, establishing these age-dependent changes in humans has been challenging. Here, we describe a multimodal stra...

Background: The impact that the absence of expression of NeuGc in pigs might have on pig organ or cell transplantation in humans has been studied in vitro, but only using red blood cells (pRBCs) and peripheral blood mononuclear cells (pPBMCs) as the target cells for immune assays. We have extended this work in various in vitro models and now repor...

In 2009, the International Xenotransplantation Association (IXA) published a consensus document that provided guidelines and "recommendations" (not regulations) for those contemplating clinical trials of porcine islet transplantation. These guidelines included the IXA's opinion on what constituted "rigorous pre-clinical studies using the most relev...

Derailment of immune responses can lead to autoimmune type 1 diabetes and this can be accelerated or even induced by local stress caused by inflammation or infection. Dendritic cells (DCs) shape both innate and adaptive immune responses. Here, we report on the responses of naturally occurring human myeloid BDCA1(+) DCs towards differentially stress...

T cells target peptide combos One of the enduring mysteries of autoimmunity is the identity of the specific proteins targeted by autoimmune T cells. Delong et al. used mass spectrometry to elucidate the peptide targets of autoimmune T cells isolated from a mouse model of type 1 diabetes. T cells targeted hybrid peptides formed by the covalent linki...

Transplantation of islets into the gastric submucosal space (GSMS) has several advantages (e.g., avoidance of the instant blood-mediated inflammatory response [IBMIR], ability to biopsy). The aim of this study was to determine whether endoscopic biopsy of islet allografts transplanted into the GSMS in diabetic pigs can provide histopathological and...

The immunologic barriers to successful xenotransplantation are related to the presence of natural anti-pig antibodies in humans and non-human primates that bind to antigens expressed on the transplanted pig organ (the most important of which is galactose-α1,3-galactose [Gal]), and activate the complement cascade, which results in rapid destruction...