Organ transplantation is a rapidly evolving field of surgery and medicine. The early days of experimentation have passed and organ transplantation is now a routine and successful option in the treatment of many diseases. Yet, further advancement is essential to make each transplant a complete success, particularly with the current shortage of donor organs. A multidisciplinary approach is required as further advancements demand insights, not only in surgical techniques, but also in traditional scientific disciplines such as immunology, physiology, pharmacology, and cell biology. Here at UCSF, faculty and fellows perform basic research in these fields, often in collaboration with scientists from other disciplines.
The following is a brief overview of several ongoing projects and an explanation of their importance to transplantation.
Long-Term Clinical Outcomes in Kidney Donors
Exploration of Avenues to Desensitize Patients with Anti-HLA Antibodies
Acute Organ Injury during Transplantation
Improving the Allocation of a Scarce but Lifesaving Resource - The Donor Liver
Of Mice and Men” Mouse Model to Prevent Human Rejection to Transplanted Organs
Achieving Transplantation Tolerance through Immune Regulation
Treg Cells: A Novel Means to Promote Kidney Transplant Survival
Immunosuppression Withdrawal for Pediatric Living-Donor Liver Transplant Recipients
Andrew M. Posselt, MD
Dr. Andrew M. Posselt specializes in adult and pediatric kidney, liver and pancreas transplantation, laparoscopic donor nephrectomy, and laparoscopic as well as open bariatric surgery. In addition to caring for patients on the transplant and bariatric surgery services, he is involved in the following research activities: 1. Clinical Transplantation of Pancreatic Islets: The Pancreatic Islet Group at UCSF is involved in several multi-center trials examining the efficacy of pancreatic islet transplantation as treatment for type 1 diabetes mellitus. These studies include use of novel immunosuppressive agents and islet transplantation in diabetic patients who have already received a kidney transplant for end-stage diabetic kidney disease. 2. Assessment of Long-Term Clinical Outcomes in Kidney Donors: There is emerging evidence that some kidney donor groups may be at higher risk for developing renal dysfunction after donation.
Dr. Posselt and his associates have accumulated a comprehensive database of patients who donated a kidney at UCSF; this database goes back as far as 1967, the year the UCSF program was established. These donors are being contacted and many have already been recruited in a study which evaluates their kidney function and overall health. 3. Clinical Outcomes of Bariatric Surgery in Patients with End Stage Kidney of Liver Disease: Many potential transplant candidates are excluded from transplantation because they are obese. Unfortunately, most of these patients will not able to lose the required weight on their own. Dr. Posselt has initiated a clinical project which examines the applicability of bariatric surgery as treatment for obesity in patients awaiting organ transplant. Preliminary results show that this approach is safe and very effective in promoting weight loss; several patients who underwent this procedure have lost the required weight and are now awaiting organ transplantation.
Exploration of Avenues to Desensitize Patients with Anti-HLA Antibodies
Deborah Adey, MD
Dr. Adey’s primary research focus over the past few years has been in managing patients who have developed antibodies against human tissue and are awaiting a kidney transplant. Potential recipients can develop antibodies (i.e. become sensitized) to other human tissue as a result of blood transfusion, previous organ transplantation, pregnancy, and in rare circumstances infection. The development of antibodies against human tissue can severely limit the possibility of proceeding with a successful renal transplant.
Dr. Adey and her colleagues have explored the use of intravenous gammaglobulin (IVIG) in selected patients to inhibit the circulating antibodies present in sensitized individuals. These investigations require intense collaboration between the physicians, the immunogentics laboratory, the surgeons, the nurse coordinators, and the patients. UCSF has now successfully transplanted approximately 20 individuals over the past 2-3 years. No severe rejections have occurred and no renal allografts have been lost.
The other major area of investigation for Dr. Adey is in the area of BK nephropathy, also known as polyoma. Polyoma virus can cause damage to kidney transplants in about 3-5% of patients. The presence of BK virus can be an indicator of over immunosuppression. Dr. Adey is a co-chair of a National Institutes of Health (NIH) multi-center study to compare decreasing immunosuppression alone versus decreasing immunosuppression in conjunction with using an intravenous medicine called cidofovir for treating BK nephropathy.
Acute Organ Injury during TransplantationClaus Niemann, MD
The liver and kidney are formidable organs. They have innumerable essential and vital functions, and surgery of the liver and kidney is fraught with danger, due to the complex anatomy, and the sizable blood vessels that run to, through and away from the liver and kidney. However, when organs are transplanted both, liver and kidney, sometimes do not function well. Organ donor factors such obesity and advanced age, as well the time without oxygen to the organ play important roles. For example, obesity is a major problem that in growing rapidly in the United States. Between 1999 and 2000 an estimated 31% of the US population was considered obese.
Obesity is associated with an increasing number of associated conditions including diabetes and high blood pressure. Organ transplantation will increasingly rely on this potential organ donor pool to meet the increasing demand. While significant research efforts are under way to modulate the immune response (immunosuppression) of organ recipients, there is still a very poor understanding why organs may not function in the first place. In Dr. Niemann’s laboratory, he and his colleagues are focused on studying the reasons why organs do not function under certain conditions and are so susceptible to ischemic (as a result of decreased blood flow) injury. They utilize animal models to mimic what actually occurs in liver and kidney transplantation.
The organs are then studied, using state of the art techniques, including looking at different genes, proteins and metabolites that are involved in producing the injury as well as those that may protect from injury. Dr. Niemann and his colleagues are examining the role of circulating white blood cells from the bloodstream that are called in when there is injury, and may play a role in making that injury worse.
They are also studying the molecular signals and the substances that alert these white cells to come into an area of injury. By elucidating these mechanisms, they will be able to identify potential areas to intervene so that the injury to organs becomes less severe, and thus their patients who undergo liver or kidney transplantation may have better survival rates and tolerate this potentially life saving procedure in a better and safer manner. Their clinical research is based on their findings in the laboratory and aims to apply this knowledge directly to patients. As known from diabetes, elevated glucose levels are detrimental to organs.
Other than factors already mentioned above, they have very recently demonstrated that even extremely transient blood glucose elevations (as little as 2 hours) causes severe renal injury in the animal when exposed to surgical stress. Dr. Niemann and his colleagues aim to implement a strict glucose control in the immediate pre-surgical, surgical and post-surgical period for all organ donors and recipients of liver and kidney transplantation. This is of enormous importance, especially in organs that are considered at risk of not functioning properly.
Improving the Allocation of a Scarce but Lifesaving Resource — The Donor LiverScott William Biggins, MD
Donor livers for liver transplantation are a scarce, life-saving resource. For patients whose lives depend upon liver transplantation, policies for prioritizing allocation of available donor livers are of ultimate importance. In the current paradigm for prioritizing patients on the liver transplant waiting list, available donor livers are allocated based upon a “sickest first” policy. Thus, the onus is on the transplant community to continuously refine the allocation system such that livers are targeted to patients who need them most. In accordance with a mandate from the Department of Health and Human Services, donor livers are allocated in the United States in an objective and transparent manner using a mathematical equation called the MELD score or Model for End-Stage Liver Disease (MELD) score. This MELD score based allocation system works well; accurately predicting urgency for liver transplantation the vast majority (83% to 87%) of patients waiting for a donor liver. However, there are some patients with liver diseases whose survival is dependent upon factors other than the severity of the liver disease and who may not manifest derangements in the three laboratory tests that are used to calculate their MELD score. Such patients may be underserved by current MELD based policies. Dr. Biggins’ research efforts focus on improving the systems by which available donor livers are distributed to patients in need of liver transplantation. Although significant medical and surgical advances have been made in the last two decades, many patients who undergo liver transplantation will eventually develop recurrent liver disease and failure of their transplanted liver. When this occurs, repeat liver transplantation is often the only definitive treatment. At present, liver grafts are allocated for repeat transplantation using the identical system as for initial transplantation- that is, the MELD score. Unfortunately, the MELD score has been shown to be less accurate in measuring the urgency for repeated liver transplantation. As a result, many patients seeking repeat liver transplantation become too sick to undergo the procedure and must be removed from the waiting list. This phenomenon seems to be particularly true for patients who have recurrent hepatitis C infection after liver transplantation. The number of patients with hepatitis C infection in need of repeat transplantation is expected to increase four-fold in the coming decade. As a result, improved allocation policies for repeat liver transplantation, particularly for those with hepatitis C infection, are essential. Dr. Biggins’ research, generously funded by American Liver Foundation, has identified new mathematical models that may improve the prediction of urgency for repeat liver transplantation and thereby optimize the overall survival benefit of the procedure. Dr. Scott Biggins is a Transplant Hepatologist and Assistant Professor of Medicine at the University of California, San Francisco.
Of Mice and Men” Mouse Model to Prevent Human Rejection to Transplanted OrgansAdnan Jaigirdar, MD
The immune system plays a crucial role in differentiating self from non-self. This capability allows us to defend against infections and pathogens. However, after transplantation, the immune system also sees the newly transplanted organ as a foreign body and reacts to it. This response severely damages the transplanted organ resulting in rejection. Thus, unless the donor and the recipient are identical twins, rejection poses a serious threat to successful organ transplantation. Most transplant candidates do not have identical donors available, so the chances of an exact match are extremely poor. The majority of the time, we match the donor and recipient as closely as possible, and then administer drugs to the recipient to control the immune system's response. However, this also weakens the body's means to fight infection, and the medications have other non-specific side effects. Hence, studying the rejection process with scrutiny and devising means to counter this process specifically to avoid side effects is the goal of Dr. Jaigirdar’s research. This would be greatly beneficial to the transplanted organ’s survival and patient’s well-being. In order to study how rejection occurs, Dr. Jaigirdar and his colleagues have developed a unique model in mice that mimics the human immune response in their lab. Because of this model, they can precisely delineate the rejection processes to various organs such as the heart, skin, kidney, liver, small bowels and pancreatic islet cells. This specific study will hopefully allow them to precisely target pathways that lead to rejection, and avoid non-specific serious side effects. Over the past few years, under the guidance of Dr. Sang-Mo Kang, they have used this unique tool and have had significant understanding to heart and pancreatic islet cell rejection. Dr. Jaigirdar and his colleagues plan to expand their work to other organs such as small bowel and liver transplantation. In the upcoming future, they plan to devise specific means to prevent the rejection pathways using their model and then taking it to the bedside.
Achieving Transplantation Tolerance through Immune RegulationQizhi Tang, PhD
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The immune system is designed to protect us against infections and the outgrowth of cancerous cells by creating an army of cells capable of recognizing a vast array of “foreign” molecules not normally present in a healthy individual. Transplanted organs from genetically distinct donors display numerous such foreign molecules and illicit vigorous immune reactions. Transplant recipients take various immunosuppressive drugs to protect the graft from immune attack. The immunosuppressive drugs currently in clinical use blindfold the immune system and prevent it from responding to the transplanted grafts as well as infections and tumors. Cardiac graft recipients under long-term immunosuppression can develop lethal vasculopathy due to cytomegalovirus (CMV) infection. In addition, it has been estimated that the risk of developing cancer is as high as 80% after 30 years of continuous immunosuppression. Moreover, commonly used drugs such as FK506 and steroids have toxic side effects to many tissues such as kidney, bone, and islets. Thus, there is an urgent need to develop new treatment for preventing graft rejection. Ideally, the new treatment should specifically block the immune response toward the graft while preserving other responses such as those against infections and tumor cells. One of the research focuses in Dr. Tang’s laboratory is to develop new therapies for preventing graft rejection by harnessing the natural immune self-control mechanism. The immune system has many built-in mechanisms for preventing aberrant activation under healthy conditions and for avoiding excessive immune activation. Regulatory T cells are one of the major components for controlling immune responses. These cells represent less than 2% of the white blood cells in the blood, and they function very much like police of the immune system to suppress unwanted activity while allowing normal immune response to occur. People and mice with genetic defect in regulatory cells display massive immune activation, tissue destruction, organ failure, and early lethality. Partial loss of these cells has been attributed to be the underlying cause of various autoimmune diseases such as type 1 diabetes, multiple sclerosis, and lupus. These observations demonstrate the crucial importance of these regulatory T cells in normal immune homeostasis and their potent activity in controlling immune responses. In the past four years, Dr. Tang’s laboratory has developed methods to isolate the regulatory T cells and expand them in-vitro to obtain sufficient numbers for therapeutic use. We are able to prevent and even reverse type 1 diabetes using regulatory T cells in a mouse model system. In collaboration with Dr. Sang-Mo Kang, Dr. Tang and her colleagues also found that these cells were able to prolong allogeneic cardiac graft survival in mouse models. Future work in the laboratory will be aimed at 1) Defining subtypes of regulatory T cells that exhibit most potent inhibitory functions on immune response against grafts; 2) Determining treatment regiments that synergize with regulatory T cells therapy; 3) Adapting the methodology to isolate and expand human regulatory T cells for pre-clinical testing.
Treg Cells: A Novel Means to Promote Kidney Transplant SurvivalJulie M. Yabu, MD
Kidney transplantation today has excellent short-term outcomes that have paralleled the use of new immunosuppressive agents introduced in the 1990s. Long-term survival rates, however, have failed to improve. Administration of immunosuppression following solid organ transplantation is essential following solid organ transplantation to prevent rejection by inhibiting an immune response, or the activation of T cells. Unfortunately, life-long administration of these drugs is accompanied by adverse effects including the increased risk of infections, malignancy, injury to the kidney transplant, and cardiovascular complications. Hence, achieving a "true" tolerance, (i.e., long-term), drug-free graft survival with normal function is of utmost importance. The ability to induce donor-specific tolerance could significantly improve long-term graft survival, reduce or eliminate the continuing need for expensive, toxic and non-specific immunosuppressive therapy and enhance the quality of life. T cell mediated regulation is one of the main mechanisms responsible for maintaining tolerance. Recent studies have highlighted the importance of a specialized subgroup of CD4+CD25+ T lymphocytes, termed regulatory T lymphocytes (Treg cells), in the suppression of autoimmunity and the development of tolerance. The effect of different immunosuppressive drugs on the development and functional activity of Treg cells is unknown. One hypothesis is that drugs that enhance the generation of Treg cells may improve the outcome of acute rejection and promote tolerance. Belatacept is a novel CD28/B7 co-stimulatory pathway inhibitor currently in Phase III clinical trials in kidney transplant patients. Current studies suggest that CD28 blockade can regulate Treg cells. Basiliximab is an anti-CD25 monoclonal antibody approved for use in kidney transplantation. Both agents have shown efficacy in preventing rejection. Dr. Yabu and her colleagues’ studies aim to examine the short and long term effects of immunosuppressive therapies on the homeostasis and function of Treg cells following kidney transplantation. Furthermore, they plan to determine whether expansion of Treg cells contributes to improved graft survival and better outcomes of acute rejection. Dr. Yabu and her colleagues believe these findings will be an exciting step in developing more novel immunosuppressive therapies that promote tolerance.
Immunosuppression Withdrawal for Pediatric Living-Donor Liver Transplant RecipientsSharon Blaschka, NP
UCSF and Chicago Children's Memorial are the two sites for this study. Between the two sites, 20 participants will be enrolled. After extensive screening with both labs and liver biopsy, these pediatric patients will have their immunosuppression medication weaned down over a period of about nine months with the goal of complete withdrawal. Immunologic and genetic profiles will be collected at multiple time points and compared between tolerant and non-tolerant participants. For the first year of enrollment, the children must get their blood drawn every two weeks and after their last dose, come back for another liver biopsy to assess liver function while weaning from their medication. They will be followed for a minimum of four years after completion of immunosuppression withdrawal. Currently, transplantation of any solid organ means a lifetime of immunosuppression medication for the recipient. However, several reports support that a significant proportion of liver recipients (19% - 42%) can maintain normal function without immunosuppression – known as "functional tolerance." In addition to closely monitoring the outcome of immunosuppression withdrawal among these participants, a scientific effort will be made to identify donor-specific immune responses and genetic characteristics that may predict or correlate with functional tolerance. This study is proving to stir up many emotions among the patients, their families, and those of us who are involved in the study coordination. For many years, these parents and children have been educated on the crucial importance of taking this medication so that the body does not reject the liver. This responsibility can no doubt instill anxiety, worry, and even fear in a parent. Taking a daily medication has come to be a way of life for these children however, it has been observed that during adolescence it becomes more difficult as they begin to compare themselves to their peers and try to "fit in." In addition, the side effects of these medications can potentially be damaging to the kidney, for instance, over a prolonged period of time. What is learned from clinical trials is beneficial for everyone whether the trial succeeds or fails. Knowledge is gained either way. Ground-breaking research such as this can only contribute to the improvement of quality patient care and provide us with two elements that are essential to our lives: knowledge and, just as important, hope. We are excited about these projects because their results, and those of all the projects being researched within the Transplant Service at UCSF, can directly and rapidly impact how clinical transplantation is practiced. With your continued support and dedication, we will see these projects to fruition and pursue new avenues of investigation.