Harnessing local and systemic immunity for vaccines against tuberculosis.

The lung is the portal of entry for Mycobacterium tuberculosis (Mtb) and animal experimental evidence indicates that local immune defense mechanisms are crucial for protective immunity. Immunization via the lower respiratory tract efficiently induces a dividing, activated, antigen-dependent, lung-resident, memory T-cell population, which is partly recoverable by bronchoalveolar lavage. These cells can inhibit the growth of Mtb in the lungs immediately after infection. Delivery of appropriate signals to the lung innate immune system is critical for induction of effective local immunity. In contrast after parenteral immunization, antigen-specific cells may be found in lung tissue but few are recoverable by lavage and inhibition of mycobacterial growth is delayed. Harnessing both local and systemic immunity can provide highly effective protection in animal models and the evidence suggests that taken in aggregate, multiple animal models may predict the success of novel vaccine strategies in humans.

Immune memory: the basics and how to trigger an efficient long-term immune memory.

Immunological memory consists of expanded clones of T and B lymphocytes that show an increased rate of cell division and shortened telomeres compared with naïve cells. However, exhaustion of clones is delayed by kinetic heterogeneity within clones and altered survival and up-regulation of telomerase. Prolonged maintenance of protective B-cell immunity is T-cell dependent and requires a balance between plasma cells and memory B cells. Protective T-cell immunity also requires correct quality of T cells and that they are located appropriately.

Unusual case presentations associated with the CD45 C77G polymorphism.

CD45, the leucocyte common antigen, is a haematopoietic cell specific tyrosine phosphatase. Human polymorphic CD45 variants are associated with autoimmune and infectious diseases and alter the phenotype and function of lymphocytes, establishing CD45 as an important regulator of immune function. Here we report four patients with diverse diseases with unusual clinical features. All four have the C77G polymorphism of CD45 exon 4, which alters the splicing and CD45RA/CD45R0 phenotype of lymphocytes. We suggest that C77G may be a contributing factor in these unusual cases.

Altered CD45 expression in C77G carriers influences immune function and outcome of hepatitis C infection.

BACKGROUND: A polymorphism in exon 4 (C77G) of CD45 that alters CD45 splicing has been associated with autoimmune and infectious diseases in humans. OBJECTIVE: To investigate the effect of C77G in hepatitis C virus (HCV) infected individuals and study the phenotype and function of peripheral blood mononuclear cells (PBMC) from healthy and hepatitis C infected C77G carriers. RESULTS: C77G individuals showed an increased proportion of primed CD45RA and effector memory CD8 T cells and more rapid activation of the lymphocyte specific protein tyrosine kinase (Lck) following CD3 stimulation. Transgenic mice with CD45 expression mimicking that in human C77G variants had more activated/memory T cells, more rapid proliferative responses, and activation of Lck. CONCLUSIONS: Changes in CD45 isoform expression can alter immune function in human C77G variants and CD45 transgenic mice. The C77G allele may influence the outcome of HCV infection.

Immunology of vaccination.

An ideal vaccine is relatively easy to define, but few real vaccines approach the ideal and no vaccines exist for many organisms, for which a vaccine is the only realistic protective strategy in the foreseeable future. Many difficulties account for the failure to produce these vaccines. All micro-organisms deploy evasion mechanisms that interfere with effective immune responses and, for many organisms, it is not clear which immune responses provide effective protection. However, recent advances in methods for studying immune response to pathogens have provided a better understanding of immune mechanisms, including immunological memory, and led to the realisation that the initiation of immune responses is a key event requiring triggering through 'danger' signals. Based on these findings, the development of novel adjuvants, vectors and vaccine formulations allowing stimulation of optimal and prolonged protective immunity should lead to the introduction of vaccines for previously resistant organisms.

Vaccine programmes and policies.

Management of an effective national vaccine strategy necessitates careful planning. In the face of budgetary constraints and the likely development of many new vaccines over the next few years, a rational choice of which vaccines to use and how best to use them will depend on first class disease surveillance, economic analysis of cost effectiveness and mathematical modelling to ensure optimal vaccine delivery. Effective immunisation programmes require strategic planning that integrates the outputs of these parameters with available health facilities with the least possible disruption. At the present time, the greatest threat to vaccination is resistance to continuing vaccination in the face of declining prevalence of many infectious diseases and heightened fears over vaccine safety. Re-assurance of the public that vaccines are safe demands effective detection of vaccine-related side-effects and rigorous investigation of any safety concerns.