Biodegradable polymer microspheres have been used in humans for in vivo drug delivery (7), cancer chemotherapy (8), and vaccination with antigenic peptides (9). Local and sustained delivery of therapeutic agents can also be achieved with biodegradable controlled-release polymers (7). The attraction of gene-modification lies mainly in the fact that the cytokine of choice can be delivered to the tumor microenvironment in a paracrine manner, circumventing the severe side effects associated with systemic cytokine immunotherapy (1, 2, 6). The development of clinically more feasible and less expensive alternative technologies for the local and sustained delivery of cytokines to tumors can significantly enhance the clinical implementation of cytokine-based cancer immunotherapies. Although some encouraging results have been reported with cytokine gene-modified tumor cell vaccines (5), it has also become increasingly clear that with the possible exception of melanomas, the current gene transfer technologies lack the simplicity and the versatility required for universal clinical application (1, 6). Systemic bolus cytokine therapy has been associated with low efficacy and severe side effects in the clinic (4). On the basis of the successful results obtained in preclinical models, numerous Phase I and II clinical trials have been initiated in cancer patients (3). The ability of cytokines and cytokine gene-modified tumor cell vaccines to induce effective antitumor immunity in syngeneic murine tumor models is well established (1, 2). These studies establish the utility of biodegradable polymer microspheres as a clinically feasible alternative to systemic cytokine therapy and cytokine gene-modified cell vaccines for the treatment of neoplastic disease. The sustained release of IL-12 from the microspheres was superior to bolus injection of free IL-12, and intratumoral delivery of microspheres was more effective than other routes of administration. In situ tumor vaccination, i.e., injection of IL-12 microspheres into existing tumors, was superior to vaccination of mice with mixtures of tumor cells (live or irradiated) and IL-12 microspheres in inducing systemic antitumor immunity. Mice that experienced tumor regression after being treated rejected a subsequent challenge with live tumor cells, which indicated the development of systemic antitumor immunity. Treatment of tumor-bearing BALB/c mice with a single intratumoral injection of biodegradable polylactic acid microspheres loaded with recombinant interleukin-12(IL-12) promoted complete regression of the primary tumor and prevented the metastatic spread to the lung. Also a useful model for understanding the basis of increased lymphoid malignancies in immunodeficiencies as thymic lymphomas occurs in about 15% of mice.An alternative technology for the local and sustained delivery of cytokines to tumors for cancer immunotherapy was evaluated and shown here to induce tumor regression, suppression of metastasis, and development of systemic antitumor immunity.Useful model for studying the relationship between immunity and disease, studies on engraftment of xenogenic cells and tissues and studying human severe combined immunodeficiency.Macrophage activation and antigen presentation, NK cell activity and myeloid cell differentiation is normal.A variable percentage (2-20%) of young adults develops low numbers of functional B and T-cells.Although B and T-cells and pre-B and pre-T cells are absent early B and T-cells are present. Bone marrow lacks plasma cells and lymphocytes and skin lacks dendritic Thy-1 + epidermal cells.Lymphoid organs consist of vascular connective tissue and macrophages and are devoid of lymphocytes. Homozygotes have little or no immunoglobulin in serum.Prkdc scid (autosomal recessive, protein kinase, DNA activated, catalytic polypeptide). Arose as a spontaneous autosomal recessive mutation in C.B-Igh-1 b (CB-17) congenic strain.Albino ( A/ A Tyrp1 b/ Tyrp1 b Tyr c/ Tyr c)
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