Intestinal Transplantation Outcomes

Intestinal transplantation has evolved from being considered an experimental procedure into a clinically accepted therapy for patients with intestinal failure and parenteral nutrition life-threatening complications. Early referral, advances in immunosuppression therapy, standardization of surgical techniques, prophylactic therapy of infections, early diagnosis of rejection, and better posttransplant patient management are some of the changes that have allowed more patients to receive transplants, thus recovering intestinal sufficiency, and at the same time allowing the procedure to spread worldwide. Over the last 2 decades, transplant centers have focused on improving short-term patient survival, which has consequently increased by >20%. It is now clear that even though isolated intestinal-transplant recipients have lower mortality risk on the waiting list, they are at higher risk for long-term graft loss. Mortality is higher on the waiting list and early posttransplant in recipients whose intestinal transplants are associated with liver grafts; however, they have better long-term patient and graft survival. Nevertheless, 3-year actuarial patient survival has not changed over the same period of time, and therefore this is our challenge for the next decade.Fil: Gondolesi, Gabriel Eduardo. Fundación Favaloro; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Almau, Héctor M.. Fundación Favaloro; Argentin

Liver Transplantation for Metastatic Neuroendocrine Tumors

We have thoroughly read the article “Liver Transplant for Metastatic Neuroendocrine Tumors: A Single-Center Report of 15 Cases” by Moradi and colleagues, which was published in Experimental and Clinical Transplantation.1 We would like to congratulate the authors for their success in liver transplant (LT) due to metastatic neuroendocrine tumors (NETs) and their important contribution to the scientific community.The authors reported 8 LTs, 4 multivisceral transplants, 1 LT associated with a Whipple procedure, 1 liver and pancreas transplant, and 1 LT combined with ileal resection. The inclusion criteria mentioned in the article were nonresectable well-differentiated NETs with confined liver metastases of unknown origin and resectable or resected primary tumor. During the follow-up, all patients who had received multiorgan transplants died and the 8 patients who underwent LT had remained alive and disease free.Nevertheless, there are different aspects to be considered for discussion. Although the authors mentioned the inclusion criteria, it is not explained which parameters were taken into account to enlist patients as transplant candidates; in addition, not having the primary tumor resected was not considered as a contraindication. Another topic we would like to discuss are the pathological criteria that were considered as contraindications for multivisceral and LT.The simultaneous resection of the primary tumor and LT has been carefully evaluated by Le Treut and colleagues.2 They reported 213 LTs for metastatic NETs and stated that primary site tumor resection concurrent with LT was a predictor of poor outcome. Determining the origin of the primary tumor is mandatory before deciding which therapeutic option to proceed with because the primary site of NETs has also been described as a factor associated with outcomes. Some authors have stated that tumors located in the pancreas seem to be more aggressive than those of intestinal origin.5 In the study from Moradi and colleagues, most transplant recipients had a pancreatic NET, although 6 transplants were performed in patients with primary tumor with unknown origin. The manuscript did not report any information regarding the functional status of the tumors, if patients had received somatostatin analogs as part of the pretransplant management, and if there were any priority criteria for patients on the wait list. These issues must be considered since outcomes can be different for isolated liver transplants compared with multiorgan transplants. We suggest that the authors revise the indications using more selective protocols.In our center, we have established a very restricted protocol for NETs, using as reference the criteria pro-posed by Mazzaferro and colleagues6: Ki-67 of 0% to 5%, well-differentiated or moderately differentiated tumor (grade 1 or grade 2), disease confined to the liver, primary tumor resected with stable disease for at least 6 months, and, if possible, location of primary tumor limited to the small bowel. As advised by Gedaly and colleagues, patients with non-carcinoid tumors, high-grade neuroendocrine carcinomas, and non-gastrointestinal carcinoids or with tumors not drained by the portal vein are not considered for transplant.7During patient work-up, we always perform somatostatin receptor positron emission tomo-graphy/computed tomography (PET/CT) imaging to identify extrahepatic metastatic disease; this is repeated every 6 months to ensure that the disease remains in control while the patient is on the wait list. In the study from Moradi and colleagues, there was a lack of information regarding pretransplant assessment. The use of somatostatin receptor PET/CT imaging has become an essential tool, not only to better identify primary locations but also to assess grading or follow disease stability to define the next therapeutic step.From September 2009 to July 2021 at our center, 533 LT were performed: 494 with organs procured from donors after brain death (DBD) and 39 using living related donors, 35 of which were for pediatric recipients. From the total number of LTs performed at our center, 6 (1.13%) were due to nonresectable NET liver metastases; all of these patients received grafts from DBDs.Among the 6 patients with NETs at our center, no patient was considered for multiorgan transplant. The median age was 42 years (range, 35-61 y), 4 patients were female, and median body mass index (in kilograms divided by height in meters squared) was 23.2 (range, 20-26). All patients had symptoms at the moment of diagnosis. In 5 patients (83%), diagnosis of the primary tumor and the liver metastases was simultaneous; however, in the remaining patient, the diagnosis was made 1 year after the first surgery. Five patients had the primary tumor located in the small bowel: 4 underwent partial enterectomy and 1 had a right hemicolectomy, all having primary anastomosis. The sixth patient had the primary tumor on the tail of the pancreas and underwent a distal pancreatectomy. One patient underwent 2 transarterial chemoemboliza-tions before being listed for LT. No patient underwent liver resection before the transplant. In our country Argentina, additional Model for End-Stage Liver Disease (MELD) score exception (22 points) is usually granted to these patients. The median time on the waiting list was 5.5 months (range, 2-16 months). All patients had received somatostatin analogs before LT.The 6 patients with NETs received transplants from DBDs: in 4 patients, a whole graft was used, but the other 2 patients had extended right lobe split grafts. The donor risk index was >1.7 in 4/6 cases. The median operation time was 345 minutes (range, 265-513 min). Patients were hospitalized for 6.5 days (range, 5-24 days) with no immediate posttransplant complications. Tacrolimus and mycophenolate mofetil were initially used as immunosuppressive therapy. After liver function had stabilized, patients received everolimus. After a follow-up of 43 months (range, 4-82 months), 1 patient presented with recurrent disease and 1 died of sepsis while waiting for a retransplant due to ischemic cholangiopathy (this was one of the recipients of an extended right lobe graft) (Table 1).Performing LT in patients with malignant diseases is a new challenge; the latest published data have demonstrated that short-term and long-term outcomes of LT in selected patients with NET liver metastases are comparable to patients transplanted for other malignancies. The results shown by Moradi and colleagues suggested that the selection criteria for multivisceral transplantation might require further discussion, analysis, and worldwide consensus. Criteria should be conservative, aimed at the best long-term outcomes, and with the most conscious use of the limited number of donors available.Fil: Fernandez, Maria Florencia. Fundación Favaloro; ArgentinaFil: Barros Schelotto, Pablo. Fundación Favaloro; ArgentinaFil: Mendez, Guillermo. Fundación Favaloro; ArgentinaFil: Descalzi, Valeria. Fundación Favaloro; ArgentinaFil: Gondolesi, Gabriel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentin

IMPACTO DE LA TERAPIA DE INMUNOSUPRESIÓN EN LAS POBLACIONES DE LINFOCITOS T REGULATORIOS EN TRASPLANTE INTESTINAL

El trasplante intestinal (TI) se aplica en casos de insuficiencia intestinal y falla de nutrición parenteral total, siendo el rechazo del injerto la complicación más frecuente y con mayor morbimortalidad. Una mejor comprensión de los mecanismos efectores y modulatorios es necesaria para desarrollar nuevas estrategias de control de alorreactividad con una mínima dosis de inmunosupresión (IS) como mantenimiento. Por razones de toxicidad renal asociadas a la terapia inmunosupresora con tacrolimus, se evalúa la posibilidad de su reemplazo por sirolimus. Este último es capaz de bloquear la respuesta efectora sin afectar la generación de células T regulatorias (Tregs), pero aún no ha sido estudiado su impacto en la generación Tregs en el TI. Se ha reportado que la administración de un anticuerpo monoclonal aCD45RC induce tolerancia e inhibición de la respuesta humoral en un modelo de trasplante cardiaco, pero mantiene la respuesta primaria y de memoria. Si bien el TI posee una complejidad mayor, hipotetizamos que la administración de aCD45RC podría inducir tolerancia, controlando el proceso de rechazo. En el presente trabajo nuestro objetivo es analizar la dinámica de las Tregs del injerto en modelos experimentales a fin de determinar su capacidad de controlar el rechazo y definir estrategias inmunosupresoras que maximicen la respuesta regulatoria con una mínima dosis de IS de mantenimiento. En nuestro grupo contamos con un modelo murino de TI alogénico que, por su carácter heterotópico, permite caracterizar en detalle la cinética del rechazo de injerto. Para cumplir el objetivo, contamos con tres grandes grupos de animales: grupo control isogénico, se realiza el TI empleando ratas Wistar como donante y receptor; grupo control de rechazo, se realiza el TI entre ratas Sprague como donantes y Wistar como receptoras sin administración de IS; y el grupo con tratamiento, en el cual se realiza el TI alogénico con distintas terapias inmunosupresoras (monoterapia con tacrolimus, terapia combinada tacrolimus + sirolimus, tacrolimus + aCD45RC y tacrolimus + sirolimus + aCD45RC). Se llevarán a cabo scores clínicos, estudios histopatológicos por tinción con hematoxilina-eosina, cuantificación de células apoptóticas por técnica de TUNEL y expresión de genes por qPCR (IL6, CXCL1, IL22, IL-17, IFN, IL13, IDO, entre otros). Asimismo, con el objetivo de estudiar la funcionalidad del injerto se realizarán pruebas de absorción y permeabilidad para glucosa. También se aislará y caracterizará poblaciones de células T intestinales por citometría de flujo, evaluando activación (CD25+) y fenotipo (expresión de CD45RC, CD4, CD8, FOXP3, PD1, PDL1 y CD45RA). Esperamos correlacionar el éxito clínico de las distintas estrategias analizadas comparativamente con la generación de respuesta T regulatoria en el injerto, lo cual permitirá mejorar la comprensión de la relación entre los distintos tipos de inmunosupresión y la generación de respuesta regulatoria

Functional abdominal complaints occurred frequently in living liver donors after donation

Background. Donor outcome after living donor liver transplantation has not been examined extensively with regard to postoperative abdominal complaints. We wanted to examine the extent and type of abdominal complaints after removal of a part of the liver and gallbladder in living donors as well as potential similarities with known disorders. Methods. Twelve patients of mixed ethnicity, nine men, aged 18-45 years, and three women, aged 32-46 years, were enrolled in the study during a 3-year period and followed up at 6 and 12 months. Patients filled out questionnaires pertaining to functional abdominal complaints (FAC) using a recognized questionnaire, Rome II, as well as specific abdominal pain symptoms known from gallstone disease. Results. FAC occurred in 11 patients at 6 months and nine patients at 12 months while abdominal pain occurred in seven and six patients, respectively. Three patients had FAC but no abdominal pain while two patients had no complaints at 12 months. Irritable bowel syndrome (IBS) was found in the majority of patients. Conclusions. FAC and pain seemed to indicate a general postoperative disorder, of a psychosomatic character, and not connected with removal of part of the liver and gallbladder in particular. However, the occurrence of IBS and FD should merit attention, as they are known to impair quality of life.Fil: Søndenaa, Karl. University of Bergen; NoruegaFil: Gondolesi, Gabriel Eduardo. Fundación Favaloro; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Roayaie, Sasan. No especifíca;Fil: Goldman, Jody S.. No especifíca;Fil: Hausken, Trygve. University of Bergen; NoruegaFil: Schwartz, Myron E.. No especifíca

Four years of experience in the use of multidetector computer tomography in pancreas transplantation: a lesson learned together with surgeons

Objetivo. Conocer la anatomía normal posquirúrgica del paciente con trasplante de páncreas en tomografía computada multidetector (TCMD) y describir las complicaciones más frecuentes. Revisión de tema. El trasplante pancreático ha aumentado en los últimos años como estrategia terapéutica en pacientes diabéticos, siendo en la actualidad el único tratamiento eventualmente curativo. Según cifras del Instituto Nacional Central Único Coordinador de Ablación e Implante (INCUCAI), en el 2001 se realizaron 9 trasplantes renopancreáticos/pancreáticos, mientras que en el 2011 se practicaron 74. Esto nos obliga como radiólogos a conocer la anatomía normal posquirúrgica y a aprender a identificar las complicaciones más frecuentes. Los métodos imagenológicos utilizados son la ecografía/Doppler, la tomografía computada multidetector (TCMD), la angiografía convencional y la resonancia magnética (RM). En pacientes con buena función renal y ecografía no concluyente, para categorizar las complicaciones, la evaluación por tomografía computada multidetector es el paso siguiente. En nuestro hospital se realizaron 25 trasplantes pancreáticos en el período 2008-2012. Durante el posoperatorio, en 19 de ellos se sospecharon, por clínica o ecografía, complicaciones (a 15 de los cuales se les realizó tomografía computada). Conociendo la técnica quirúrgica, describimos la anatomía normal y desarrollamos las complicaciones posquirúrgicas más frecuentes: vasculares (trombosis, fístula arteriovenosa, pseudoaneurisma) y no vasculares (pancreatitis, fístulas pancreáticas, colecciones, neumoperitoneo, íleo). Conclusión. La tomografía computada multidetector es un método de gran utilidad al momento de evaluar pacientes con trasplante pancreático. Un conocimiento cabal de la particular anatomía posquirúrgica y sus posibles complicaciones es crucial para el radiólogo, con el fin de orientar el seguimiento y tratamiento de estos pacientes.Purpose. To gain knowledge of normal postoperative findings on Multidetector Computed Tomography (MDCT) in patients with pancreas transplant and describe the most frequent complications. Topic review. Pancreatic transplantation is currently the only definitive treatment for diabetic patients. In recent years, its use has increased as therapeutic strategy. According to the INCUCAI, in 2001 9 transplants were performed, increasing to 74 in 2011. This increase creates a need for radiologists to gain knowledge of the normal postoperative anatomy and learn to identify the most frequent postoperative complications. The imaging methods used are Doppler / ultrasound, MDCT, conventional angiography and MRI. In patients with good renal function in whom ultrasound is not diagnostic for characterization of complications, the next step is MDCT. At our hospital, 25 pancreatic transplants were performed in 2008-2012. Postoperative complications were suspected clinically or by ultrasound in 19 of them. Fifteen of them were evaluated by CT for further characterization Imaging findings or procedure details. As we learn the surgical techniques that were performed, normal images are described, allowing a correct interpretation of MDCT findings in these patients. The most common post operative complications were: - Vascular: thrombosis, arteriovenous fistula, pseudoaneurysm - Non vascular: pancreatitis, pancreatic fistulas, collections, pneumoperitoneum, ileus. Conclusion: MDCT is a useful method for assessing patients with pancreas transplantation. A clear understanding of the unique anatomy and possible postoperative complications is crucial for the radiologist to guide the monitoring and treatment of this patient.Fil: Paladín, Hugo José. Fundación Favaloro; ArgentinaFil: Neira Sepúlveda, Angela Patricia. Fundación Favaloro; ArgentinaFil: González, Maria Bernardina. Fundación Favaloro; ArgentinaFil: Ramisch, Diego. Fundación Favaloro; ArgentinaFil: Gondolesi, Gabriel Eduardo. Fundación Favaloro; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Haberman, Diego Mariano. Fundación Favaloro; Argentin

Paneth and Intestinal Stem Cells Preserve their Functional Integrity during Worsening of Acute Cellular Rejection in Small Bowel Transplantation

Graft survival after small bowel transplantation remains impaired due to acute cellular rejection (ACR), the leading cause of graft loss. Although it was shown that the number of enteroendocrine progenitor cells in intestinal crypts was reduced during mild ACR, no results of Paneth and intestinal stem cells localized at the crypt bottom have been shown so far. Therefore, we wanted to elucidate integrity and functionality of the Paneth and stem cells during different degrees of ACR, and to assess whether these cells are the primary targets of the rejection process. We compared biopsies from ITx patients with no, mild or moderate ACR by immunohistochemistry and quantitative PCR. Our results show that numbers of Paneth and stem cells remain constant in all study groups, whereas the transit-amplifying zone is the most impaired zone during ACR. We detected an unchanged level of antimicrobial peptides in Paneth cells and similar numbers of Ki-67+ IL-22R+ stem cells revealing cell functionality in moderate ACR samples. We conclude that Paneth and stem cells are not primary target cells during ACR. IL-22R+ Ki-67+ stem cells might be an interesting target cell population for protection and regeneration of the epithelial monolayer during/after a severe ACR in ITx patients.Fil: Pucci Molineris, Melisa Eliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Gonzalez Polo, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Pérez, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Ramisch, D.. Fundación Favaloro; ArgentinaFil: Rumbo, Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Gondolesi, Gabriel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Meier, D.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentin

Analysis of immune cells draining from the abdominal cavity as a novel tool to study intestinal transplant immunobiology

Summary During intestinal transplant (ITx) operation, intestinal lymphatics are not reconstituted. Consequently, trafficking immune cells drain freely into the abdominal cavity. Our aim was to evaluate whether leucocytes migrating from a transplanted intestine could be recovered from the abdominal draining fluid collected by a peritoneal drainage system in the early post-ITx period, and to determine potential applications of the assessment of draining cellular populations. The cell composition of the abdominal draining fluid was analysed during the first 11 post-ITx days. Using flow cytometry, immune cells from blood and draining fluid samples obtained the same day showed an almost complete lymphopenia in peripheral blood, whereas CD3+CD4+CD8 -, CD3+CD4-CD8+ and human leucocyte antigen D-related (HLA-DR)+CD19+ lymphocytes were the main populations in the draining fluid. Non-complicated recipients evolved from a mixed leucocyte pattern including granulocytes, monocytes and lymphocytes to an exclusively lymphocytic pattern along the first post-ITx week. At days 1-2 post-Itx, analysis by short tandem repeats fingerprinting of CD3 +CD8+ sorted T cells from draining fluid indicated that 50% of cells were from graft origin, whereas by day 11 post-ITx this proportion decreased to fewer than 1%. Our results show for the first time that the abdominal drainage fluid contains mainly immune cells trafficking from the implanted intestine, providing the opportunity to sample lymphocytes draining from the grafted organ along the post-ITx period. Therefore, this analysis may provide information useful for understanding ITx immunobiology and eventually could also be of interest for clinical management.Laboratorio de Investigaciones del Sistema Inmun

Paneth and intestinal stem cells preserve their functional integrity during worsening of acute cellular rejection in small bowel transplantation

Graft survival after small bowel transplantation remains impaired due to acute cellular rejection (ACR), the leading cause of graft loss. Although it was shown that the number of enteroendocrine progenitor cells in intestinal crypts was reduced during mild ACR, no results of Paneth and intestinal stem cells localized at the crypt bottom have been shown so far. Therefore, we wanted to elucidate integrity and functionality of the Paneth and stem cells during different degrees of ACR, and to assess whether these cells are the primary targets of the rejection process. We compared biopsies from ITx patients with no, mild or moderate ACR by immunohistochemistry and quantitative PCR. Our results show that numbers of Paneth and stem cells remain constant in all study groups, whereas the transit-amplifying zone is the most impaired zone during ACR. We detected an unchanged level of antimicrobial peptides in Paneth cells and similar numbers of Ki-67+ IL-22R+ stem cells revealing cell functionality in moderate ACR samples. We conclude that Paneth and stem cells are not primary target cells during ACR. IL-22R+ Ki-67+ stem cells might be an interesting target cell population for protection and regeneration of the epithelial monolayer during/after a severe ACR in ITx patients.Instituto de Estudios Inmunológicos y Fisiopatológico

Neo-Suprahepatic cava: A case report of a modified technique for domino liver transplantation

Domino liver transplantation, introduced in 1997, originally consisted of a graft from a patient with familial amyloidotic polyneuropathy used as a donor for a compatible recipient, thus increasing the pool of hepatic grafts for liver transplantation. The aim of this report was to present a modification on the technique for outflow reconstruction in domino liver transplantation first proposed by Liu et al and Cescon et al. In this description we proposed a new technique that differs from the one mentioned above by performing a neo-suprahepatic cava, constructed using only an iliac vein graft, facilitating the anastomosis as if it was a regular cadaveric liver transplant.Fil: Padín, J. M.. Fundación Favaloro; ArgentinaFil: Pfaffen, G.. Fundación Favaloro; ArgentinaFil: Pérez Fernández, I.. Fundación Favaloro; ArgentinaFil: Sandi, M.. Fundación Favaloro; ArgentinaFil: Ramisch, D.. Fundación Favaloro; ArgentinaFil: Barros Schelotto, P.. Fundación Favaloro; ArgentinaFil: Gondolesi, Gabriel Eduardo. Fundación Favaloro; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Analysis of immune cells draining from the abdominal cavity as a novel tool to study intestinal transplant immunobiology

Summary During intestinal transplant (ITx) operation, intestinal lymphatics are not reconstituted. Consequently, trafficking immune cells drain freely into the abdominal cavity. Our aim was to evaluate whether leucocytes migrating from a transplanted intestine could be recovered from the abdominal draining fluid collected by a peritoneal drainage system in the early post-ITx period, and to determine potential applications of the assessment of draining cellular populations. The cell composition of the abdominal draining fluid was analysed during the first 11 post-ITx days. Using flow cytometry, immune cells from blood and draining fluid samples obtained the same day showed an almost complete lymphopenia in peripheral blood, whereas CD3+CD4+CD8 -, CD3+CD4-CD8+ and human leucocyte antigen D-related (HLA-DR)+CD19+ lymphocytes were the main populations in the draining fluid. Non-complicated recipients evolved from a mixed leucocyte pattern including granulocytes, monocytes and lymphocytes to an exclusively lymphocytic pattern along the first post-ITx week. At days 1-2 post-Itx, analysis by short tandem repeats fingerprinting of CD3 +CD8+ sorted T cells from draining fluid indicated that 50% of cells were from graft origin, whereas by day 11 post-ITx this proportion decreased to fewer than 1%. Our results show for the first time that the abdominal drainage fluid contains mainly immune cells trafficking from the implanted intestine, providing the opportunity to sample lymphocytes draining from the grafted organ along the post-ITx period. Therefore, this analysis may provide information useful for understanding ITx immunobiology and eventually could also be of interest for clinical management.Laboratorio de Investigaciones del Sistema Inmun