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Journal of the Anatomical Society of India

Plenary Lecture

Author(s): Dr. N. N. Mehra, Dr. Muddanna S. Rao, Dr. Jerome Kalister

Vol. 56, No. 1 (2007-01 - 2007-06)

Hematopietic Stem Transplantation: Challenges and Limitations

Dr. N. N. Mehra, Professor and Head Department of Transplant Immunology and Immunogentics, All India Institute of Medical Sciences, New Delhi 110 029, India

Hematopoeitic stem cell transplantation (HSCT) is a proven remedial modality for hematologic, malignancies. The success of HSCT has been achieved through a better understanding of the immunobiology of the human leucocyte antigen (HLA) system and through more precise and comprehensive immunogenetic matching of recipients with their potential donors. It has been established that the severity and outcome of transplant related immunological reaction as well as the overall graft survival are predominantly determined by the set of immune response genes clustered together as the HLA system, which is an analogue of the major histocompatibility complex (MHC) in man. The extensive polymorphism of HLA genes confers important biological implications affecting engraftment. graft-versus-host (GVHD) and overall survival.

Four inherent features of the MHC extraordinary high polymorphism, tight among various loci, nonrandom association of alleles, and its multi-peptide binding ability make the system of particular interest in biology and medicine. The MHC molecules bind peptide fragments derived from protein antigens (viruses bacterial peptides, mismatched transplant antigens etc) and display them on the surface of antigen presenting cells (APCs) evoking effector responses. Since the number of peptides that can naturally be generated is very large, there is a biological need for an extensive MHC gene pool. Nevertheless, the ploymorphism of MHC genes poses major difficulties for donor selection since it is often difficult to select a suitably matched donor for transplantation.

Although the genetic compatibility between donor and the recipient is a critical factor for the success of a stem cell transplant, other factors also influence graft survival to a variable degree. These include original disease of the patient, pretransplant conditioning, donor source and the number of stem cells transfused, presence or absence of donor T cells in the infusion, post transplant immune suppression therapy and stability of chirmerism established.

The success of HSCT is governed by a complex set of often competing variables that can obscure the relationship between HLA matching and eventual graft outcome. The availability of matched donors for patients lacking an HLA-genotypically matched sibling has been greatly augmented through high resolution DNA based HLA typing and though establishment of international registries of voluntary stem cell donors. Similarly, the development of methods that reliably achieve complete engraftment of donor lymphohematopoiesis without subjecting patients to high-does toxic chemoradiothereapy represents an important step in capitalizing on the allogeneic graft-versus-tumr effect. Currently, allogeneic BMT is being perceived as an immunotherapeutic approach, rather than solely a vehicle to deliver high-dose therapy.

The underlying mechanisms that mediate induction of donor specific tolerance and failitate engraftment are complex but tempting for investigations and therapeutic applications. Future advances in unrelated donor transplantation must include the identification of tolerable HLA mismatches, so that more patients may benefit from this therapeutic modality. Greater understanding of genetic polymorphism of other immune response genes like cytokines, chemokines and adhesion molecules, NK cells receptors and others affecting drug metabolism, normal and malignant tissue sensitivity, and their potential to respond the therapy is also crucial. The bigger challenges is to develop effector molecules with a capacity to specifically block the allo T cell responses without compromising general immune surveillance of the host.

Plenary Lecture – II

Temporal Lobe Epilepsy and Fetal Neural Stem Cell Transplanation

Dr. Muddanna S. Rao,
Department of Anatomy, KMC, Manipal

Temporal lobe epilepsy (TLE) is characterized by progressive increase in spontaneous recurrent motor seizures (SRMS). The links among the extent of hippocampal neurodegeneration, the frequency of SRMS and degree of aberrant mossy fiber sprouting are the issues under discussion. In F344 rats an attempt was made to study the relation between spontaneous recurrent motor seizure and neurodegeneration, aberrant mossy fiber sprouting. Ability of fetal and stem cells to differentiate in the epileptic hippocampus was also attempted. In these rats status epilepticus was induced by graded injection of low doses of Kainic acid (KA). KA was administered every I hours for 4 hours for a cumulative does of 10.5 mg/kg body weight to induce continuous state III-IV motor seizure for more than 3 hours. Structural changes in the hippocampus was studied at an early time point (4th day) and late time point (5 months after KA injection) and correlated with extent of seizure. At 4 days post K.A. majority of rats (77%) exhibited moderate bilateral neurodegenaration in different regions of the hippocampus 2.2% of rats exhibited massive neurodegenaration in all hippocampal regions. All the KA treated rats displayed robust SRMS at 3 months post KA and severity of SRMS increased over time. Occurrence of SRMS was associated with considerable bilateral hippocampal neurodegeneration and abbrrant mossy fiber sprouting.

To assess the utility of fetal and neural stem cells as a therapy for epilepsy these cells were transplanted into chronically epileptic hippocampus. Fetal cells were selected from 18 days old fetus and neural stem cells were isolated from neonatal hippocampus and cultured for 8-10 days. Both types of cells found to be well differentiated and integrated structurally and functionally with the host hippocampus. These cell transplants appear to be very promising as cell therapy for treatment of epilepsy.

Plenary Lecture – III

Volumetric Anatomy – An introduction

Dr. Jerome Kalister

The anatomical positions of organs and spaces in the body have been traditionally described in relation to one another. This approach is quite crude for locating an internal organ or space in the body. This is totally idea of where something is located. Advancements in medical and surgical procedures demand a far more accurate approach in defining a point in the body. An absolute system of locating, positioning or naming the position of a space or mass in the body does not exist.

The concept of volumetric Anatomy defines a point in the body in the 3D space using three intersecting planes. The point achieved is very very specific for an organ. A 3D grid is superimposed into the whole volume of the body. Each organ may be positioned with reference to the nearest intersecting points. Thus the entire body may be mapped to a very high level of accuracy. These points may very with age, sex, race etc. This problem could easily be solved by linking the individual in question to the Anthropometric data that is available in extensive detail today, with a digital system that can bring in the appropriate correction factor.

The applications of having extreme accuracy in locating any point in the body with a computer assistance should be quite vast, right from the diagnostic insertion of a needle into any part of the body to the much fantasised telesurgery.

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