Clinical Transplantation Studies Research Articles

Novel agents or strategies for immunosuppression after renal transplantation

There have been several recent advances in the use of immunosuppression after organ transplantation. The main goal is to induce transplantation tolerance without immunosuppressive drug toxicity. We reviewed both experimental and clinical organ transplantation studies such as costimulatory blockade agents, sphingosine 1-phosphate receptor analogs, lymphocyte depletion strategies, and chemokine blockade agents in the context of renal transplantation. The newer and safer immunosuppression protocols might provide significant benefit to organ transplant recipients as alternatives to conventional immunosuppressive therapy.

PEDIATRIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

The successful use of allogeneic HSCT for children with malignant and nonmalignant diseases continues to be limited by the development of acute and chronic GVHD, infectious complications, delayed recovery of the immune system, acute and long-term toxicity, and relapse of disease. Significant advances have been made, particularly in the ability to identify suitable sources of HSC. Future advances will depend on a better understanding of the biology of HSC sources, GVHD, immune reconstitution, and common complications. Improved therapies are dependent on participation of children in well-designed, translational and clinical transplant studies.

Somatic Delivery of Catecholamines in the Striatum Attenuate Parkinsonian Symptoms and Widen the Therapeutic Window of Oral Sinemet in Rats

Guidelines for clinical transplantation studies for Parkinson's disease emphasize that transplants should be considered as an adjunct to systemicl-DOPA, yet few preclinical studies have specifically assessed the potential of transplants as an adjunct to the clinical gold standard treatment. The objectives of the present study were to determine if encapsulated PC12 cells implanted in rats with severe unilateral dopamine depletions: (i) have a direct therapeutic effect on measures of parkinsonian symptoms; and/or (ii) increase the therapeutic window of oral sinemet in this model. Rats with severe unilateral dopamine depletions received striatal implants of encapsulated PC12 cells producing dopamine andl-DOPA. These rats were tested on a battery of behavioral measures of parkinsonian symptoms, at a range of doses of oral sinemet (0, 12, 24, and 36 mg/kg). Stereotypies/dyskinesias were also quantified after high doses of oral sinemet (36 and 50 mg/kg). The results confirm that parkinsonian symptoms can be quantified in rats with severe dopamine depletions, and the validity and clinical relevance of these measures are supported by the fact that the clinical gold standard treatment, oral sinemet, attenuates these parkinsonian symptoms. Somatic delivery of dopamine andl-DOPA, directly to the dopamine-depleted striatum, also attenuates parkinsonian symptoms. In fact, the magnitude of the therapeutic effect produced by continuous, site-specific, somatic delivery of dopamine andl-DOPA was larger than the effect produced by acute, systemic, oral sinemet. The beneficial effects of oral sinemet and striatal implants of catecholamine-producing devices were additive, but there were no adverse effects related to striatal catecholamine-producing devices, and these devices did not increase the adverse effects related to oral sinemet. Therefore, striatal implants of catecholamine-producing devices have direct therapeutic effects which are fairly robust, and they widen the therapeutic window of oral sinemet.

Canine CD34: Cloning of the cDNA and Evaluation of an Antiserum to Recombinant Protein

Increasingly, enriched populations of hematopoietic progenitors are used in experimental and clinical transplantation studies. The separation of progenitors is based on the expression of CD34, a marker preferentially expressed on progenitor cells. The dog model has been important for preclinical transplant studies, because it has proven predictive for outcomes in human hematopoietic stem cell transplantation. To identify and isolate canine hematopoietic progenitors, we have cloned a cDNA encoding a CD34 homologue from a canine myelomonocytic leukemia cell line, ML2. The CD34 homologue cDNA predicts an amino acid sequence that is highly conserved with human and murine CD34 in the cytoplasmic domain, transmembrane domain, and C-terminal end of the extracellular domain, but shows considerable divergence from these sequences at the amino-terminal end of the protein. In Western blotting studies, canine CD34 homologue (caCD34) appears to be a heavily and variably glycosylated protein with a molecular weight of approximately 100 kD and shows some tissue-specific differences in protein mass. To evaluate the expression of caCD34 protein, the extracellular domain of caCD34 was expressed as an Ig fusion protein and used as an immunogen to generate a rabbit polyclonal antiserum. The antiserum reacted against the fusion protein, against vascular endothelium, and with three leukemic cell lines. Approximately 1% of canine bone marrow cells stained brightly with antibodies to caCD34 and this population was 25- to 50-fold enriched for colony-forming units-granulocyte-macrophage as compared to unfractionated marrow mononuclear cells. These findings suggest that the canine CD34 homologue is expressed on bone marrow progenitor cells and, thus, that this molecule should be a valuable marker for identifying and isolating canine hematopoietic progenitors for experimental hematopoiesis and stem cell transplantation.

The kidney and primary hypertension: contributions from renal transplantation studies in animals and humans

In clinical renal transplantation studies, recipients of a renal graft from a donor with a genetic predisposition to hypertension had higher blood pressures and required more antihypertensive treatment than recipients of a renal graft from a normotensive donor. In addition, blood pressure normalization in patients suffering from essential hypertension by bilateral nephrectomy and subsequent transplantation of a kidney from a normotensive donor has been reported. The interpretation of these data may be limited by the large number of different factors that can contribute to post-transplantation hypertension in human renal transplant recipients. In experimental renal transplantation studies the contribution of individual factors to post-transplantation hypertension can be independently assessed. Besides immunological graft rejection and hypertension-induced damage to the renal graft, a genetic predisposition to hypertension in the kidney donor has been demonstrated to be associated with post-transplantation hypertension in the recipient. Thus, normotensive recipients of a renal graft from a genetically hypertensive donor consistently developed post-transplantation hypertension in four different animal models of genetic hypertension. Furthermore, in genetically hypertensive rats bilateral nephrectomy together with transplantation of a kidney from a normotensive donor has been shown to be associated with a decrease in blood pressure. Hypertension following renal transplantation may be due to a variety of factors, including immunological graft rejection, hypertension-induced damage to the renal transplant and a genetic predisposition to hypertension of the kidney donor. The finding that blood pressure is transplanted with the renal graft in genetic hypertension suggests a genetically determined alteration to the kidney as a major factor in the aetiology of primary hypertension. The nature of this factor is just beginning to be understood. Renal transplantation studies in rat models of genetic hypertension, combined with the tools of molecular biology, may help to provide further insights into the role of the kidney in primary hypertension.

The Clinical Role of OKT3

The murine monoclonal anti-T-cell antibody, OKT3, has been used during the past 9 years in various clinical transplantation studies. Its use in clinical organ transplantation has advanced the science of MoAb use in humans and has provided a vast amount of evidence substantiating the importance of MoAbs in clinical medicine. Undoubtedly OKT3 has proven to be the most effective and specific immunosuppressive drug widely available for use in organ transplantation.

The Clinical Role of OKT3

The murine monoclonal anti-T-cell antibody, OKT3, has been used during the past 9 years in various clinical transplantation studies. Its use in clinical organ transplantation has advanced the science of MoAb use in humans and has provided a vast amount of evidence substantiating the importance of MoAbs in clinical medicine. Undoubtedly OKT3 has proven to be the most effective and specific immunosuppressive drug widely available for use in organ transplantation.

Partial hepatic autotransplantation with complete revascularization in the dog.

AUXILIARY homotransplantation of the liver raises several problems apart from those having to do with immunosuppression. Revascularization of the transplanted liver is complicated by the dual hepatic blood supply. Most of the evidence obtained from homotransplantation studies suggests that splanchnic venous blood must perfuse the portal bed of the transplant for long-term hepatocyte integrity. 1-3 These results, however, are somewhat confused by the effects of required hepatotoxic immunosuppressive agents. Experiments using partial portacaval transpositions have yielded conflicting results 4,5 in regard to the role of portal blood. A reliable source of donor hepatic tissue has remained a major obstacle in clinical transplantation studies. It has been suggested that a part of the human liver from a live donor might serve as a life supporting transplant. 6 A technique of partial hepatic autotransplantation with complete revascularization was developed in the dog in an attempt to answer certain aspects of these problems.